Kinase inhibitors

ABSTRACT

There are provided compounds of formula I, 
                         
wherein T, A, Q, Z, G, R 4 , R 5a , R 5b  and n have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

This invention relates, inter alia, to compounds which areantiinflammatory agents (e.g. through inhibition of one or more ofmembers of: the family of p38 mitogen-activated protein kinase enzymes(referred to herein as p38 MAP kinase inhibitors), for example the alphakinase sub-type thereof; Syk kinase; and the Src family of tyrosinekinases). The invention also relates to the use of such compounds intherapy, including in mono- and combination therapies, especially in thetreatment of inflammatory diseases, including inflammatory diseases ofthe lung (such as asthma and chronic obstructive pulmonary disease(COPD)), eye (such as uveitis or keratoconjunctivitis sicca (dry eyedisease, also known as xerophthalmia)) and gastrointestinal tract (suchas Crohn's disease and ulcerative colitis).

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively) havebeen identified, each displaying different patterns of tissueexpression. The p38 MAPK alpha and beta isoforms are found ubiquitouslythroughout the body, are present in many different cell types and areinhibited by a number of previously described small molecular weightcompounds. Early classes of inhibitors were highly toxic due to thebroad tissue distribution of these isoforms which resulted in off-targeteffects of the compounds. Some of the more recently identifiedinhibitors show improved selectivity for p38 MAPK alpha and betaisoforms and have wider safety margins.

p38 MAP kinase is believed to play a pivotal role in many of thesignalling pathways that are involved in initiating and maintainingchronic, persistent inflammation in human disease, for example, insevere asthma, COPD and inflammatory bowel disease (IBD). There is nowan abundant literature which demonstrates that p38 MAP kinase isactivated by a range of pro-inflammatory cytokines and that itsactivation results in the recruitment and release of furtherpro-inflammatory cytokines. Indeed, data from some clinical studiesdemonstrate beneficial changes in disease activity in patients duringtreatment with p38 MAP kinase inhibitors. For instance, Smith describesthe inhibitory effect of p38 MAP kinase inhibitors on TNFα (but notIL-8) release from human PBMCs (Smith, S. J., Br. J. Pharmacol., 2006,149:393-404).

The use of inhibitors of p38 MAP kinase in the treatment of COPD and IBDhas also been proposed. Small molecule inhibitors targeted to p38MAPKα/β have proved to be effective in reducing various parameters ofinflammation in:

-   -   cells and tissues obtained from patients with COPD, who are        generally corticosteroid insensitive (Smith, S. J., Br. J.        Pharmacol., 2006, 149:393-404);    -   biopsies from IBD patients (Docena, G. et al., J. Trans.        Immunol., 2010, 162:108-115); and    -   in vivo animal models (Underwood, D. C. et al., Am. J. Physiol.,        2000, 279:L895-902; Nath, P. et al., Eur. J. Pharmacol., 2006,        544:160-167).

Irusen and colleagues also suggested the possibility of involvement ofp38 MAPKα/β on corticosteroid insensitivity via the reduction of bindingaffinity of the glucocorticoid receptor (GR) in nuclei (Irusen, E. etal., J. Allergy Clin. Immunol., 2002, 109:649-657). Clinicalinvestigations in inflammatory diseases with a range of p38 MAP kinaseinhibitors, including AMG548, BIRB 796, VX702, SCIO469 and SCIO323, havebeen described (Lee, M. R. and Dominguez, C., Current Med. Chem., 2005,12:2979-2994.). However, the major obstacle hindering the utility of p38MAP kinase inhibitors in the treatment of human chronic inflammatorydiseases has been the toxicity observed in patients. This has beensufficiently severe to result in the withdrawal from clinicaldevelopment of many of the compounds progressed, including all thosespecifically mentioned above.

COPD is a condition in which the underlying inflammation is reported tobe substantially resistant to the anti-inflammatory effects of inhaledcorticosteroids. Consequently, a superior strategy for treating COPDwould be to develop an intervention which has both inherentanti-inflammatory effects and the ability to increase the sensitivity ofthe lung tissues of COPD patients to inhaled corticosteroids. The recentpublication of Mercado et al. (2007; American Thoracic Society AbstractA56) demonstrates that silencing p38 MAPK γ has the potential to restoresensitivity to corticosteroids. Thus, there may be a dual benefit forpatients in the use of a p38 MAP kinase inhibitor for the treatment ofCOPD.

Many patients diagnosed with asthma or with COPD continue to suffer fromuncontrolled symptoms and from exacerbations of their medical conditionthat can result in hospitalisation. This occurs despite the use of themost advanced, currently available treatment regimens, comprising ofcombination products of an inhaled corticosteroid and a long actingβ-agonist. Data accumulated over the last decade indicates that afailure to manage effectively the underlying inflammatory component ofthe disease in the lung is the most likely reason that exacerbationsoccur. Given the established efficacy of corticosteroids asanti-inflammatory agents and, in particular, of inhaled corticosteroidsin the treatment of asthma, these findings have provoked intenseinvestigation. Resulting studies have identified that some environmentalinsults invoke corticosteroid-insensitive inflammatory changes inpatients' lungs. An example is the response arising fromvirally-mediated upper respiratory tract infections (URTI), which haveparticular significance in increasing morbidity associated with asthmaand COPD.

It has been disclosed previously that compounds that inhibit theactivity of both the c-Src and Syk kinases are effective agents againstrhinovirus replication (Charron, C. E. et al., WO 2011/158042) and thatcompounds that inhibit p59-HCK are effective against influenza virusreplication (Charron, C. E. et al., WO 2011/070369). Taken together withinhibition of p38 MAPK, these are particularly attractive properties forcompounds to possess that are intended to treat patients with chronicrespiratory diseases.

Certain p38 MAPK inhibitors have also been described as inhibitors ofreplication of respiratory syncytial virus (Cass L. et al., WO2011/158039).

The precise etiology of IBD is uncertain, but is believed to be governedby genetic and environmental factors that interact to promote anexcessive and poorly controlled mucosal inflammatory response directedagainst components of the luminal microflora. This response is mediatedthrough infiltration of inflammatory neutrophils, dendritic cells andT-cells from the periphery. p38 has become an obvious target forinvestigation in IBD models as a consequence of its ubiquitousexpression in inflammatory cells. Studies investigating the efficacy ofp38 inhibitors in animal models of IBD and human biopsies from IBDpatients indicated that p38 could be a target for the treatment of IBD(Hove, T. ten et al., Gut, 2002, 50:507-512, Docena, G. et al., J.Trans. Immunol., 2010, 162:108-115). However, these findings are notcompletely consistent with other groups reporting no effect with p38inhibitors (Malamut G. et al., Dig. Dis. Sci, 2006, 51:1443-1453). Aclinical study in Crohn's patients using the p38 alpha inhibitor BIRB796demonstrated potential clinical benefit with an improvement inC-reactive protein levels. However this improvement was transient,returning to baseline by week 8 (Schreiber, S. et al., Clin. Gastro.Hepatology, 2006, 4:325-334). A small clinical study investigating theefficacy of CNI-1493, a p38 and Jnk inhibitor, in patients with severeCrohn's disease showed significant improvement in clinical score over 8weeks (Hommes. D. et al. Gastroenterology. 2002 122:7-14).

T cells are known to play a key role in mediating inflammation of thegastrointestinal tract. Pioneering work by Powrie and colleaguesdemonstrated that transfer of naive CD4+ cells into severely compromisedimmunodeficient (SCID) animals results in the development of colitiswhich is dependent on the presence of commensal bacteria (Powrie F. etal. Int Immunol. 1993 5:1461-71). Furthermore, investigation of mucosalmembranes from IBD patients showed an upregulation of CD4+ cells whichwere either Th1 (IFNγ/IL-2) or Th2 (IL5/TGFβ) biased depending onwhether the patient had Crohn's disease or ulcerative colitis (Fuss I J.et al. J Immunol. 1996 157:1261-70.). Similarly, T cells are known toplay a key role in inflammatory disorders of the eye with severalstudies reporting increased levels of T cell associated cytokines (IL-17and IL-23) in sera of Beçhets patients (Chi W. et al. Invest OphthalmolVis Sci. 2008 49:3058-64). In support of these observations, Direskeneliand colleagues demonstrated that Beçhets patients have increased Th17cells and decreased Treg cells in their peripheral blood (Direskeneli H.et al. J Allergy Clin Immunol. 2011 128:665-6).

One approach to inhibit T cell activation is to target kinases which areinvolved in activation of the T cell receptor signalling complex. Sykand Src family kinases are known to play a key role in this pathway,where Src family kinases, Fyn and Lck, are the first signallingmolecules to be activated downstream of the T cell receptor (Barber E K.et al. PNAS 1989, 86:3277-81). They initiate the tyrosinephosphorylation of the T cell receptor leading to the recruitment of theSyk family kinase, ZAP-70. Animal studies have shown that ZAP-70knockout results in a SCID phenotype (Chan A C. et al. Science. 1994,10; 264(5165):1599-601).

A clinical trial in rheumatoid arthritis patients with the Syk inhibitorFostamatinib demonstrated the potential of Syk as an anti-inflammatorytarget with patients showing improved clinical outcome and reduced serumlevels of IL-6 and MMP-3 (Weinblatt M E. et al. Arthritis Rheum. 200858:3309-18). Syk kinase is widely expressed in cells of thehematopoietic system, most notably in B cells and mature T cells.Through interaction with immunoreceptor tyrosine-based activation motifs(ITAM), it plays an important role in regulating T cell and B cellexpansion as well as mediating immune-receptor signalling ininflammatory cells. Syk activation leads to IL-6 and MMPrelease—inflammatory mediators commonly found upregulated ininflammatory disorders including IBD and rheumatoid arthritis (Wang Y D.et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al.Cytokine. 2006 January 33:106-10).

In addition to playing key roles in cell signalling events which controlthe activity of pro-inflammatory pathways, kinase enzymes are now alsorecognised to regulate the activity of a range of cellular functions,including the maintenance of DNA integrity (Shilo, Y. Nature ReviewsCancer, 2003, 3: 155-168) and co-ordination of the complex processes ofcell division. Indeed, certain kinase inhibitors (the so-called“Olaharski kinases”) have been found to alter the frequency ofmicronucleus formation in vitro (Olaharski, A. J. et al., PLoS Comput.Biol., 2009, 5(7), e1000446; doi: 10.1371/journal.pcbi.1000446).Micronucleus formation is implicated in, or associated with, disruptionof mitotic processes and is therefore undesirable. Inhibition ofglycogen synthase kinase 3α (GSK3α) was found to be a particularlysignificant factor that increases the likelihood of a kinase inhibitorpromoting micronucleus formation. Also, inhibition of the kinase GSK3βwith RNAi has been reported to promote micronucleus formation (Tighe, A.et al., BMC Cell Biology, 2007, 8:34).

Whilst it may be possible to attenuate the adverse effects of inhibitionof Olaharski kinases such as GSK3α by optimisation of the dose and/or bychanging the route of administration of a molecule, it would beadvantageous to identify further therapeutically useful molecules withlow or negligible inhibition of Olaharski kinases, such as GSK 3α and/orhave low or negligible disruption of mitotic processes (e.g. as measuredin a mitosis assay).

Various compounds, including urea derivatives, are disclosed asinhibiting one or more kinases. Examples of such compounds may be foundin WO 99/23091, WO 00/041698, WO 00/043384, WO 00/055139, WO 01/36403,WO 01/4115, WO 02/083628, WO 02/083642, WO 02/092576, WO 02/096876, WO2003/005999, WO 2003/068223, WO 2003/068228, WO 2003/072569, WO2004/014870, WO 2004/113352, WO 2005/005396, WO 2005/018624, WO2005/023761, WO 2005/044825, WO 2006/015775, WO 2006/043090, WO2007/004749, WO 2007/053394, WO 2013/050756, WO 2013/050757, WO2014/027209, WO 2014/033446, WO 2014/033447, WO 2014/033448, WO2014/033449, WO 2014/076484, WO 2014/140582 WO 2014/162121, WO2014/162122, WO 2014/162126, WO 2015/092423, WO 2015/121444, WO2015/121660 WO 2016/051187 and WO 2016/051188. Further examples may befound in articles published in:

-   -   Curr. Opin. Drug Devel. (2004, 7(5), 600-616);    -   J. Med. Chem. (2007. 50, 4016-4026; 2009, 52, 3881-3891; 2010,        53, 5639-5655; and 2016, 59, 1727-1746);    -   Bioorg. Med. Chem. Lett. (2007, 17, 354-357; 2008, 18,        3251-3255; 2009, 19, 2386-2391; and 2010, 20, 4819-4824);    -   Curr. Top. Med. Chem. (2008, 8, 1452-1467);    -   Bioorg. Med. Chem. (2010, 18, 5738-5748);    -   Eur. J. Pharmacol. (2010, 632, 93-102);    -   J. Chem. Inf. Model. (2011, 51, 115-129);    -   Br. J. Pharmacol. (2015, 172, 3805-3816); and    -   Inflamm. Bowel Dis. (2016, 22, 1306-1315).

Nevertheless, there remains a need to identify and develop new kinaseinhibitors, specifically alternative p38 MAP kinase inhibitors that aresuitable for the treatment of inflammation. There is particularly a needfor such inhibitors that have improved therapeutic potential overcurrently available treatments or, in particular, that exhibit asuperior therapeutic index (e.g. inhibitors that are at least equallyefficacious and, in one or more respects, are less toxic at the relevanttherapeutic dose than previous agents).

We have now discovered, surprisingly, that certain aniline-substituteddiarylureas inhibit one or more of p38 MAP kinase, Syk and Src familykinases and therefore possess good anti-inflammatory properties.

Thus, according to a first aspect of the invention, there is provided acompound of formula I,

-   wherein:-   T represents

-   W represents O, S or NCH₃;-   V represents N or CR¹;-   R¹ represents C₁₋₃ alkoxy, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl,    which latter four groups are optionally substituted by one or more    substituents selected from halo, hydroxy and C₁₋₂ alkoxy, or R¹    represents H;-   R² represents —NR^(A1)S(O)₂R^(B1), —S(O)₁₋₂R^(B2),    —P(O)R^(B3)R^(B4), —C(O)NR^(A2)R^(A3) or —CH₂NR^(A4)C(O)R^(A5);-   R^(A1) to R^(A5) independently represent H or C₁₋₃ alkyl optionally    substituted by one or more substituents selected from halo, hydroxy,    NR^(C)R^(D) and C₁₋₂ alkoxy, or R^(A2) and R^(A3) together represent    C₃₋₆ n-alkylene or C₄₋₅ n-alkylene interrupted between C2 and C3 by    —O—, —S(O)_(q)— or —N(R^(E))—;-   R^(B1) to R^(B4) independently represent C₁₋₃ alkyl or C₃₋₆    cycloalkyl, which latter two groups are optionally substituted by    one or more halo substituents;-   R^(C) and R^(D) independently represent H or C₁₋₃ alkyl, which    latter substituent is optionally substituted by hydroxyl or C₁₋₂    alkoxy, or R^(C) and R^(D) together combine to form C₄₋₆ alkylene    optionally interrupted between C2 and C3 by —O—, —S(O)_(q)— or    —N(R^(E))—;-   R^(E) represents H or methyl;-   q represents 0, 1 or 2;-   R³ represents C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl or C₃₋₇    cycloalkyl, which latter four groups are optionally substituted by    hydroxyl, C₁₋₂ alkoxy or halo, or R³ represents morpholinyl or    trimethylsilyl;-   A represents CH or N;-   R⁴ represents C₁₋₃ alkoxy, C₃₋₅ cycloalkoxy, or C₁₋₃ alkyl, which    latter three groups are optionally substituted by one or more halo    substituents, or R⁴ represents ethynyl, cyano, S(O)₂CH₃, halo or H:-   Q represents O, S(O)_(p), SO₂N(R⁶) or C(O)N(R⁶);-   n represents 1, 2 or 3;-   p represents 0, 1 or 2;-   R^(5a) and R^(5b) independently represent H, methyl or halo, or    R^(5a) and R^(5b) together represent C₂₋₆ n-alkylene;-   when n represents 1, Z represents O, S or NR⁷ or,-   when n represents 2 or 3, Z represents either    -   an O-atom on each occurrence, or    -   either an S-atom or NR⁷ on one occurrence and an O-atom on each        other occurrence;-   R⁶ and R⁷ independently represent H or methyl;-   G represents —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H or a carboxylic acid    isostere;-   r represents 0 or, when Het¹ is attached to (CH₂)_(r) via a ring    heteroatom, r may alternatively represent 1; and-   Het¹ represents    -   a 5- or 6-membered heterocyclic group that is fully aromatic,        which group contains one or more heteroatoms selected from N, O        and S or    -   a 4- to 7-membered heterocyclic group that is fully saturated or        partially unsaturated, and is monocyclic or is fused or bridged        bicyclic, which group contains one or more heteroatoms selected        from N, O and S,-   wherein Het¹ is optionally substituted by one or more substituents    selected from C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, hydroxyl and oxo,-   or a pharmaceutically acceptable salt thereof,-   which compounds may be referred to hereinafter as “the compounds of    the invention”.

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound of formula I with one or more equivalents of anappropriate acid or base, optionally in a solvent, or in a medium inwhich the salt is insoluble, followed by removal of said solvent, orsaid medium, using standard techniques (e.g. in vacuo, by freeze-dryingor by filtration). Salts may also be prepared by exchanging acounter-ion of a compound of formula I in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals.

For the avoidance of doubt, compounds of formula I may contain thestated atoms in any of their natural or non-natural isotopic forms. Inthis respect, embodiments of the invention that may be mentioned includethose in which:

-   (a) the compound of formula I is not isotopically enriched or    labelled with respect to any atoms of the compound; and-   (b) the compound of formula I is isotopically enriched or labelled    with respect to one or more atoms of the compound.

References herein to an “isotopic derivative” relate to the second ofthese two embodiments. In particular embodiments of the invention, thecompound of formula I is isotopically enriched or labelled (with respectto one or more atoms of the compound) with one or more stable isotopes.Thus, the compounds of the invention that may be mentioned include, forexample, compounds of formula I that are isotopically enriched orlabelled with one or more atoms such as deuterium or the like.

Compounds of formula I may exhibit tautomerism. All tautomeric forms andmixtures thereof are included within the scope of the invention.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms, be branched. Particular alkylgroups that may be mentioned include, for example, methyl, ethyl,n-propyl, iso-propyl, butyl, n-butyl and tert-butyl. Particular alkoxygroups that may be mentioned include, for example, methoxy, ethoxy,propoxy, and butoxy.

Unless otherwise specified, cycloalkyl groups as defined herein may,when there is a sufficient number (i.e. a minimum of four) of carbonatoms, be part cyclic/acyclic.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched. In particular embodiments of theinvention, alkylene refers to straight-chain alkylene.

For the avoidance of doubt, oxo substituents that may be present onheterocyclic groups represented by Het¹ may be attached to anyappropriate atoms in the heterocyclic ring including, where valenciesallow, to C-, N- and/or S-atoms within the ring (thereby forming keto,N-oxide, S(O) and/or S(O)₂ groups).

Het¹ groups that may be mentioned include the following, where thepositions of attachment specified are to the C(R^(5a))(R^(5b)) and —CO₂Hgroups of the compound of formula I: furanyl (e.g. furanyl attached atthe 2 and 4 or, particularly, 2 and 5 positions), oxadiazolyl (e.g.oxadiazolyl, such as 1,2,4-oxadiazolyl, attached at the 3 and 5positions), pyrazolyl (e.g. pyrazolyl, such as pyrazolyl or3-methylpyrazolyl, attached at the 1 and 4 positions), pyridazinyl (e.g.pyridazinyl attached at the 3 and 6 positions), pyrrolyl (e.g. pyrrolyl,such as 1-methylpyrrolyl, attached at the 2 and 5 positions),tetrahydrofuranyl (e.g. tetrahydrofuranyl attached at the 2 and 4 or,particularly, 2 and 5 positions) and thienyl (e.g. thienyl attached atthe 2 and 4 or 2 and 5 positions).

Unless otherwise specified, the term “halo” includes references tofluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo,especially fluoro or chloro.

When used herein in connection with the group G, the term “carboxylicacid isostere” includes references to carboxylic acid isosteres known tothose skilled in the art, such as those disclosed in Lassalas et al., J.Med. Chem. (2016), 59, 3183-3203, Ballatore et al., Chem. Med. Chem.(2013), 8(3), 385-395 and Boyd et al., Bioorg. Med. Chem. Lett. (2015),25, 1990-1994, the disclosures of which documents are herebyincorporated by reference.

Thus, carboxylic acid isosteres that G may represent include:

-   (a) a phosphonic or phosphinic acid moiety, or a salt thereof, such    as —P(O)(OH)₂ or —P(O)(H)(OH);-   (b) a sulfonic or sulfinic acid moiety, or a salt thereof, such as    —S(O)₂(OH) or —S(O)(OH);-   (c) a hydroxamic acid, or a salt thereof, such as —C(O)N(H)OH or    —N(C(O)CH₃)OH;-   (d) a hydroxamic acid ester, such as —C(O)N(H)OCH₃ or    —O—N(H)—C(O)CH₃;-   (e) a sulfonamide, such as —S(O)₂NH₂ or —N(H)—S(O)₂CH₃;-   (f) an acylsulfonamide, such as —C(O)N(H)—S(O)₂CH₃, or an    acylsulfamide, such as —C(O)N(H)—S(O)₂N(CH₃)₂ or —C(O)N(H)—S(O)₂NH₂;-   (g) an acylurea, such as —N(H)C(O)N(H)—C(O)CH₃;-   (h) a sulfonylurea, such as —N(H)C(O)N(H)—S(O)₂CH₃;-   (i) an electron-poor phenol moiety, such as a 2,6-difluorophenol    (e.g. attached to the rest of the molecule via the 3- or 4-position    on the phenyl ring);-   (j) —S(O)₀₋₂-phenol (e.g. where the phenol moiety is attached to the    S-atom via the 2-position of the phenyl ring);-   (k) —C(H)(OH)CF₃ or —C(O)CF₃ (or a hydrated form thereof,    —C(OH)₂CF₃);-   (l) a 3- or 4-hydroxyquinoline-2-one;-   (m) a tetrazole;-   (n) a hydroxy-, thio- or oxo-substituted, 4- or 5-membered    heterocycle that is fully aromatic, partially unsaturated or fully    saturated, which group contains one or more heteroatoms selected    from N, O and S, for example a hydroxy- or oxo-substituted    heterocyclic group selected from a thiazolidinedione, an    oxazolidinedione, a thiazolidinone, an oxazolidinone, a    thiadiazolinone, an oxadiazole-5(4H)-thione, an    oxathiadiazole-2-oxide, or a hydroxy-substituted isoxazole,    isothiazole or oxadiazole; or-   (o) a carbocyclic acid, such as tetronic acid, tetramic acid, a    cyclopentane-1,3-dione, a cyclopentane-1,2-dione, and squaric acid,    which latter group is optionally attached to the rest of the    molecule via a —N(H)— moiety.

For example, the carboxylic acid isostere may be any of the moietiesmentioned at (a) to (I) above or a cyclic moiety selected from:

or a tautomer thereof, wherein X¹ represents O or S and X² represents Oor NH.

Particular carboxylic acid isosteres that may be mentioned includetetrazolyl, acylsulfonamides, such as —C(O)N(H)—S(O)₂CH₃,acylsulfamides, such as —C(O)N(H)—S(O)₂N(CH₃)₂, a hydroxy-substitutedisoxazole, such as:

or a tautomer thereof, such as

or a 5-hydroxy-substituted 1,2,4-oxadiazole, such as:

or a tautomer thereof, such as

Embodiments of the invention that may be mentioned include those inwhich:

-   (a) T represents

-   (b) R⁴ represents C₁₋₃ alkoxy or C₁₋₃ alkyl, which latter two groups    are optionally substituted by one or more halo substituents, or R⁴    represents ethynyl, cyano, S(O)₂CH₃, halo or H;-   (c) R^(5a) and R^(5b) independently represent H, methyl or halo;-   (d) Z represents an O-atom on each occurrence; and-   (e) G represents —C(O)₂H.

In such embodiments, the compound of formula I may be represented as acompound of formula Ix,

in which:

-   R¹ to R³, A and Q are as defined above;-   R⁴ represents C₁₋₃ alkoxy or C₁₋₃ alkyl, which latter two groups are    optionally substituted by one or more halo substituents, or R⁴    represents ethynyl, cyano, S(O)₂CH_(a), halo or H; and-   R^(5a) and R^(5b) independently represent H, methyl or halo.

Other embodiments of the invention that may be mentioned include thosein which one or more of the following definitions apply to the compoundsof formula I:

-   (a1) T represents

-   (b1) R⁴ represents C₃₋₅ cycloalkoxy optionally substituted by one or    more halo substituents;-   (c1) R⁵ and R^(5b) together represent C₂₋₆ n-alkylene;-   (d1) when n represents 2 or 3, Z represents either an S-atom or NR⁷    on one occurrence and an O-atom on each other occurrence;-   (e1) G represents —[(CH₂)_(r)-Het¹]-C(O)₂H or a carboxylic acid    isostere.

In particular, embodiments of the invention that may be mentionedinclude those in which any one or, any two of, any three of, any four ofor all of (a1) to (e1) above apply.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I or Ix:

-   (a) W represents O;-   (b) V represents N;-   (c) R¹ represents deuterated C₁₋₂ alkoxy (e.g. OCD₃) or,    particularly, C₁₋₂ alkoxy or H;-   (d) R² represents —P(O)R^(B3)R^(B4), —S(O)₂R^(B2) or, particularly,    —NR^(A1)S(O)₂R^(B1) (e.g. —NHS(O)₂R^(B1)), —S(O)R^(B2) or    —C(O)NHR^(A2);-   (e) R^(A1) to R^(A5) independently represent H or methyl optionally    substituted by one or more halo substituents;-   (f) R^(B1) to R^(B4) independently represent C₁₋₂ alkyl optionally    substituted by one or more halo substituents;-   (g) R³ represents C₃₋₅ alkyl, C₃₋₆ alkynyl or trimethylsilyl;-   (h) A represents N or, particularly, CH;-   (i) R⁴ represents C₃₋₄ cycloalkoxy or, particularly, ethynyl, cyano,    halo, C₁₋₂ alkoxy or C₁₋₂ alkyl, which latter two groups are    optionally substituted by one or more halo substituents;-   (j) Q represents S, SO₂N(R⁶) or, particularly, C(O)NH, S(O), S(O)₂    or O;-   (k) n represents 1 or, particularly, 2 or 3;-   (l) p represents 0 or, particularly, 1 or 2;-   (m) R^(5a) and R^(5b) together represent —(CH₂)₂₋₄- or,    particularly, R^(5a) and R^(5b) independently represent H or methyl;-   (n) Z represents an O atom (on each occurrence) or, when n    represents 2 or 3, Z may alternatively represents either an S-atom    on one occurrence and an O-atom on each other occurrence (e.g. on    each occurrence, Z represents an O atom);-   (o) G represents a carboxylic acid isostere (e.g. as defined above),    —(CH₂)-Het¹-C(O)₂H, -Het¹-C(O)₂H or, particularly, —C(O)₂H;-   (p) Het¹ represents    -   a 5- or 6-membered heterocyclic group that is fully aromatic,        which group contains one to three heteroatoms selected from N, O        and S (e.g. Het¹ represents furanyl, oxadiazolyl (such as        1,2,4-oxadiazolyl), pyrazolyl, pyridazinyl, pyrrolyl or thienyl)        or    -   a 5- or 6-membered heterocyclic group that is fully saturated or        partially unsaturated, and is monocyclic or is fused or bridged        bicyclic, which group contains one or two heteroatoms selected        from N, O and S (e.g. Het¹ represents tetrahydrofuranyl),    -   wherein Het¹ is optionally substituted by one or more        substituents selected from C₁₋₂ alkyl, hydroxyl and oxo (e.g.        wherein Het¹ is optionally substituted by one or more methyl        groups).

Embodiments of the invention that may be mentioned include those inwhich the compound of formula I or Ix is a compound of formula Ia,

wherein R¹ to R⁴, A, Q and n are as hereinbefore defined.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I, Ix and Ia:

-   (a) R¹ represents deuterated methoxy (e.g. OCD₃) or, particularly,    methoxy;-   (b) R² represents —C(O)NH₂, —C(O)NHCH₃, —S(O)₁₋₂CH₃, —S(O)₁₋₂CH₂CH₃,    —P(O)(CH₃)₂, —N(CH₃)S(O)₂CH₃, —NHS(O)₂CH₂CH₃ or —NHS(O)₂CH₃ (e.g.    —C(O)NH₂, —C(O)NHCH₃, —S(O)CH₃ or, particularly, —NHS(O)₂CH₃);-   (c) R³ represents trimethylsilyl or, particularly, —C(CH₃)₂—R,    wherein R represents ethynyl or, particularly, methyl (e.g. R³    represents tert-butyl);-   (d) A represents N or, particularly, CH;-   (e) R⁴ represents cyclopropoxy or methoxy, which latter group is    optionally substituted by one or more halo substituents (e.g.    methoxy optionally substituted by one or more (e.g. two or three)    fluoro substituents), or, particularly, R⁴ represents methoxy;-   (f) Q represents S or, particularly, C(O)NH, S(O), S(O)₂ or O;-   (g) n represents 3 or, particularly, 2;-   (h) R^(5a) and R^(5b) together represent —(CH₂)₂— or, particularly,    R^(5a) and R^(5b) independently represent H or methyl (e.g. R^(5a)    represents H and R^(5b) represents methyl, R^(5a) and R^(5b) both    represent methyl or, particularly, R^(5a) and R^(5b) both represent    H);-   (i) G represents —CO₂H or -Het¹-CO₂H, wherein the -Het¹-CO₂H moiety    is a structural fragment selected from

-   -   or G represents a carboxylic acid isostere selected from        tetrazolyl, —C(O)N(H)—S(O)₂CH₃, —C(O)N(H)—S(O)₂N(CH₃)₂,

-   -   or a tautomer of any of the latter three groups.

Further embodiments of the invention that may be mentioned include thosein which the compound of formula I, Ix or Ia is a compound of formulaIb,

wherein R², A, Q and n are as hereinbefore defined.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I, Ix, Ia and Ib:

-   (a) R² represents —NHS(O)₂CH₃;-   (d) A represents CH;-   (e) Q represents C(O)NH, S(O), S(O)₂ or, particularly, O;-   (g) n represents 2.

In this respect, particular embodiments of the invention that may bementioned include those in which the compound of formula I is a compoundof formula Iy,

or a pharmaceutically acceptable salt thereof.

Other compounds of formula I, Ix, Iy, Ia or Ib that may be mentionedinclude the compounds of the examples described hereinafter. Thus,embodiments of the invention that may be mentioned include those inwhich the compound of formula I, Ia or Ib is a compound selected fromthe list:

-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfinyl)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yloxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethyl)phenoxy)ethoxy)ethoxy)acetic    acid;-   6-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)pyridazine-3-carboxylic    acid;-   5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-1,2,4-oxadiazole-3-carboxylic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-cyclopropoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   1-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)cyclopropane-1-carboxylic    acid;-   4-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-2-carboxylic    acid;-   1-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-3-methyl-1H-pyrazole-4-carboxylic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethylphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-(methoxy-d3)-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-N-(methylsulfonyl)acetamide;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(dimethylphosphoryl)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   5-(2-(3-((4-((4-(3-(5-(tert-buty)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)oxy)amino)-5-methoxyphenoxy)ethoxy)methyl)furan-3-carboxylic    acid;-   5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)tetrahydrofuran-3-carboxylic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(ethylsulfonyl)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(ethylsulfonamido)-2-methoxyphenyl)    ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-2,5-dihydroisoxazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide;-   2-((2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)thio)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic    acid, (R)-isomer,-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic    acid, (S)-isomer;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-2-methylpropanoic    acid;-   1-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic    acid;-   N-(3-(3-(4-((2-((3-(2-(2-((1H-tetrazol-5-yl)methoxy)ethoxy)ethoxy)-5-methoxyphenyl)amino)-pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)methanesulfonamide;-   2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-N—(N,N-dimethylsulfamoyl)acetamide;-   5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-2-carboxylic    acid;-   5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-3-carboxylic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(difluoromethoxy)phenoxy)ethoxy)ethoxy)acetic    acid;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynylphenoxy)ethoxy)ethoxy)acetic    acid;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)    ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethoxy)phenoxy)ethoxy)ethoxy)acetic    acid;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((3-oxo-2,3-dihydroisoxazol-5-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide;    and-   5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-1-methyl-1H-pyrrole-2-carboxylic    acid,    or a pharmaceutically acceptable salt thereof.

Embodiments of the invention that may be mentioned include those inwhich the compound of formula I, Ix, Ia or Ib is as hereinbeforedefined, either

-   (a) is, or-   (b) is not-   2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic    acid, or a pharmaceutically acceptable salt thereof.

Examples of salts of compounds of formula I, Ix, Iy, Ia or Ib includeall pharmaceutically acceptable salts, such as, without limitation, acidaddition salts of strong mineral acids such as HCl, H₂SO₄ and HBr salts(e.g. HCl or HBr salts) and addition salts of strong organic acids suchas methanesulfonic acid.

Particular salts of compounds of formula I, Ix, Iy, Ia or Ib that may bementioned include hydrochloric acid salts, meglumine salts, potassiumsalts and sodium salts.

References herein to a compound of the invention (a compound of formulaI, Ix, Iy, Ia or Ib) are intended to include references to the compoundand to all pharmaceutically acceptable salts, solvates, isotopicderivatives and/or tautomers of said compound, unless the contextspecifically indicates otherwise. In this respect, solvates that may bementioned include hydrates.

The compounds of the invention (compounds of formula I, Ix, Iy, Ia orIb) are p38 MAP kinase inhibitors (especially of the alpha subtype) andare therefore useful in medicine, in particular for the treatment ofinflammatory diseases. Further aspects of the invention that may bementioned therefore include the following.

-   (a) A pharmaceutical formulation comprising a compound of formula I,    Ix, Iy, Ia or Ib, as hereinbefore defined, or pharmaceutically    acceptable salt thereof, in admixture with a pharmaceutically    acceptable adjuvant, diluent or carrier.-   (b) A combination product comprising    -   (A) a compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore        defined, or pharmaceutically acceptable salt thereof, and    -   (B) another therapeutic agent,    -   wherein each of components (A) and (B) is formulated in        admixture with a pharmaceutically-acceptable adjuvant, diluent        or carrier.    -   In this aspect of the invention, the combination product may be        either a single (combination) pharmaceutical formulation or a        kit-of-parts.    -   Thus, this aspect of the invention encompasses a pharmaceutical        formulation including a compound of formula I, lx, Iy, Ia or Ib,        as hereinbefore defined, or pharmaceutically acceptable salt        thereof, and another therapeutic agent, in admixture with a        pharmaceutically acceptable adjuvant, diluent or carrier (which        formulation is hereinafter referred to as a “combined        preparation”).    -   It also encompasses a kit of parts comprising components:    -   (i) a pharmaceutical formulation including a compound of formula        I, Ix, Iy, Ia or Ib, as hereinbefore defined, or        pharmaceutically acceptable salt thereof, in admixture with a        pharmaceutically acceptable adjuvant, diluent or carrier; and    -   (ii) a pharmaceutical formulation including another therapeutic        agent, in admixture with a pharmaceutically-acceptable adjuvant,        diluent or carrier,    -   which components (i) and (ii) are each provided in a form that        is suitable for administration in conjunction with the other.    -   Component (i) of the kit of parts is thus component (A) above in        admixture with a pharmaceutically acceptable adjuvant, diluent        or carrier. Similarly, component (ii) is component (B) above in        admixture with a pharmaceutically acceptable adjuvant, diluent        or carrier.-   (c) A process for preparing the pharmaceutical formulation of    aspect (a) above, said process comprising the step of admixing the    compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, with a pharmaceutically    acceptable adjuvant, diluent or carrier.    -   Embodiments of this aspect of the invention that may be        mentioned include those in which the pharmaceutically acceptable        adjuvant, diluent or carrier is a topically acceptable adjuvant,        diluent or carrier (and/or wherein the process is for preparing        a topical pharmaceutical formulation, i.e. a pharmaceutical        formulation that is adapted for topical administration).-   (d) A compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore    defined, or pharmaceutically acceptable salt thereof, for use in    medicine (or for use as a medicament or as a pharmaceutical).-   (e) A compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore    defined, or pharmaceutically acceptable salt thereof, or a    pharmaceutical formulation or combination product as defined in    connection with aspect (a) or (b) of the invention, for use in the    treatment or prevention of an inflammatory disease.-   (f) The use of    -   a compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore        defined, or pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention,    -   for the preparation of a medicament for the treatment or        prevention of an inflammatory disease.-   (g) A method of treating or preventing an inflammatory disease, said    method comprising administering to a subject an effective amount of    -   a compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore        defined, or pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.-   (h) A method of sensitizing a subject to the anti-inflammatory    effects of a corticosteroid, said method comprising administering to    the subject an effective amount of    -   a compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore        defined, or pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.    -   Embodiments of this aspect of the invention that may be        mentioned include those in which the subject is one who has        become refractory to the anti-inflammatory effects of a        corticosteroid.

References herein to “preventing an inflammatory disease” includereferences to preventing (or reducing the likelihood of) the recurrenceof an inflammatory disease in a subject who has previously suffered fromsuch a disease (e.g. a subject who has previously received treatment forthat disease, for example treatment according to the method described in(g) above).

Thus, still further aspects of the invention that may be mentionedinclude the following.

-   (i) A compound of formula I, Ix, Iy, Ia or b, as hereinbefore    defined, or pharmaceutically acceptable salt thereof, or a    pharmaceutical formulation or combination product as defined in    connection with aspect (a) or (b) of the invention, for use in    reducing the likelihood of the recurrence of an inflammatory disease    in a subject who has previously received treatment for that disease    (e.g. treatment with a compound of formula I, la or Ib, as    hereinbefore defined, or pharmaceutically acceptable salt thereof,    or a pharmaceutical formulation or combination product as defined in    connection with aspect (a) or (b) of the invention).-   (j) The use of    -   a compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore        defined, or pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention,    -   for the preparation of a medicament for reducing the likelihood        of the recurrence of an inflammatory disease in a subject who        has previously received treatment for that disease (e.g.        treatment with a compound of formula I, Ix, Iy, Ia or Ib, as        hereinbefore defined, or pharmaceutically acceptable salt        thereof, or a pharmaceutical formulation or combination product        as defined in connection with aspect (a) or (b) of the        invention).-   (k) A method of reducing the likelihood of the recurrence of an    inflammatory disease in a subject who has previously received    treatment for that disease (e.g. treatment with a compound of    formula I, Ix, Iy, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, or a pharmaceutical    formulation or combination product as defined in connection with    aspect (a) or (b) of the invention), said method comprising    administering to said subject an effective amount of    -   a compound of formula I, Ix, Iy, Ia or Ib, as hereinbefore        defined, or pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.        Formulations

In relation to aspects (a) and (b) above, diluents and carriers that maybe mentioned include those suitable for parenteral, oral, topical,mucosal and rectal administration.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may be prepared e.g. for parenteral, subcutaneous,intramuscular, intravenous, intra-articular, intravitreous, periocular,retrobulbar, subconjunctival, sub-Tenon, topical ocular orperi-articular administration, particularly in the form of liquidsolutions, emulsions or suspensions; for oral administration,particularly in the form of tablets or capsules, and especiallyinvolving technologies aimed at furnishing colon-targeted drug release(Patel, M. M. Expert Opin. Drug Deliv. 2011, 8 (10), 1247-1258); fortopical e.g. pulmonary or intranasal administration, particularly in theform of powders, nasal drops or aerosols and transdermal administration;for topical ocular administration, particularly in the form ofsolutions, emulsions, suspensions, ointments, implants/inserts, gels,jellies or liposomal microparticle formulations (Ghate, D.; Edelhauser,H. F. Expert Opin. Drug Deliv. 2006, 3 (2), 275-287); for ocularadministration, particularly in the form of biodegradable andnon-biodegradable implants, liposomes and nanoparticles (Thrimawithana,T. R. et al. Drug Discov. Today 2011, 16 (5/6), 270-277); for mucosaladministration e.g. to buccal, sublingual or vaginal mucosa, and forrectal administration e.g. in the form of a suppository or enema.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may conveniently be administered in unit dosage form andmay be prepared by any of the methods well-known in the pharmaceuticalart, for example as described in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., (1985). Formulations forparenteral administration may contain as excipients sterile water orsaline, alkylene glycols such as propylene glycol, polyalkylene glycolssuch as polyethylene glycol, oils of vegetable origin, hydrogenatednaphthalenes and the like. Formulations for nasal administration may besolid and may contain excipients, for example, lactose or dextran, ormay be aqueous or oily solutions for use in the form of nasal drops ormetered sprays. For buccal administration, typical excipients includesugars, calcium stearate, magnesium stearate, pregelatinised starch, andthe like.

Pharmaceutical formulations and combination products suitable for oraladministration may comprise one or more physiologically compatiblecarriers and/or excipients and may be in solid or liquid form. Tabletsand capsules may be prepared with binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrrolidone;fillers, such as lactose, sucrose, corn starch, calcium phosphate,sorbitol, or glycine; lubricants, such as magnesium stearate, talc,polyethylene glycol, or silica; and surfactants, such as sodium laurylsulfate. Liquid compositions may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose, sugarsyrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifyingagents such as lecithin, or acacia; vegetable oils such as almond oil,coconut oil, cod liver oil, or peanut oil; preservatives such asbutylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).Liquid compositions may be encapsulated in, for example, gelatin toprovide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules. Such two-piece hard shellcapsules may be made from, for example, gelatin or hydroxylpropylmethylcellulose (HPMC).

A dry shell formulation typically comprises of about 40% to 60% w/wconcentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

A compound of the invention may be administered topically (e.g. to thelung, eye or intestines). Thus, embodiments of aspects (a) and (b) abovethat may be mentioned include pharmaceutical formulations andcombination products that are adapted for topical administration. Suchformulations include those in which the excipients (including anyadjuvant, diluent and/or carrier) are topically acceptable.

Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoroethane (propellant 114), and dichlorodifluoromethane(propellant 12). Suitable HFC propellants include tetrafluoroethane(HFC-134a) and heptafluoropropane (HFC-227). The propellant typicallycomprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalationcomposition. The formulation may comprise excipients includingco-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitantrioleate and the like). Other possible excipients include polyethyleneglycol, polyvinylpyrrolidone, glycerine and the like. Aerosolformulations are packaged in canisters and a suitable dose is deliveredby means of a metering valve (e.g. as supplied by Bespak, Valois or 3Mor alternatively by Aptar, Coster or Vari).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.This may be administered by means of a nebuliser e.g. one that can behand-held and portable or for home or hospital use (i.e. non-portable).The formulation may comprise excipients such as water, buffers, tonicityadjusting agents, pH adjusting agents, surfactants and co-solvents.Suspension liquid and aerosol formulations (whether pressurised orunpressurised) will typically contain the compound of the invention infinely divided form, for example with a D₅₀ of 0.5-10 μm e.g. around 1-5μm. Particle size distributions may be represented using D₁₀, D₅₀ andD₉₀ values. The D₅₀ median value of particle size distributions isdefined as the particle size in microns that divides the distribution inhalf. The measurement derived from laser diffraction is more accuratelydescribed as a volume distribution, and consequently the D₅₀ valueobtained using this procedure is more meaningfully referred to as a Dv₅₀value (median for a volume distribution). As used herein Dv values referto particle size distributions measured using laser diffraction.Similarly, D₁₀ and D₉₀ values, used in the context of laser diffraction,are taken to mean Dv₁₀ and Dv₉₀ values and refer to the particle sizewhereby 10% of the distribution lies below the D₁₀ value, and 90% of thedistribution lies below the D₉₀ value, respectively.

Topical administration to the lung may also be achieved by use of adry-powder formulation. A dry powder formulation will contain thecompound of the disclosure in finely divided form, typically with a massmean aerodynamic diameter (MMAD) of 1-10 μm or a D₅₀ of 0.5-10 μm e.g.around 1-5 μm. Powders of the compound of the invention in finelydivided form may be prepared by a micronization process or similar sizereduction process. Micronization may be performed using a jet mill suchas those manufactured by Hosokawa Alpine. The resultant particle sizedistribution may be measured using laser diffraction (e.g. with aMalvern Mastersizer 2000S instrument). The formulation will typicallycontain a topically acceptable diluent such as lactose, glucose ormannitol (preferably lactose), usually of large particle size e.g. anMMAD of 50 μm or more, e.g. 100 μm or more or a D₅₀ of 40-150 μm. Asused herein, the term “lactose” refers to a lactose-containingcomponent, including α-lactose monohydrate, β-lactose monohydrate,α-lactose anhydrous, β-lactose anhydrous and amorphous lactose. Lactosecomponents may be processed by micronization, sieving, milling,compression, agglomeration or spray drying. Commercially available formsof lactose in various forms are also encompassed, for example Lactohale®(inhalation grade lactose; DFE Pharma), InhaLac®70 (sieved lactose fordry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose®(sieved inhalation grade lactose; DFE Pharma) products. In oneembodiment, the lactose component is selected from the group consistingof α-lactose monohydrate, α-lactose anhydrous and amorphous lactose.Preferably, the lactose is α-lactose monohydrate.

Dry powder formulations may also contain other excipients such as sodiumstearate, calcium stearate or magnesium stearate.

A dry powder formulation is typically delivered using a dry powderinhaler (DPI) device. Examples of dry powder delivery systems includeSPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. Furtherexamples of dry powder delivery systems include ECLIPSE, NEXT,ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER,MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER,TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler,MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER,GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

In one embodiment a compound of the present invention is provided in amicronized dry powder formulation, for example further comprisinglactose of a suitable grade optionally together with magnesium stearate,filled into a single dose device such as AEROLISER or filled into amulti dose device such as DISKUS.

The compounds of the present invention may also be administeredrectally, for example in the form of suppositories or enemas, whichinclude aqueous or oily solutions as well as suspensions and emulsions.Such compositions are prepared following standard procedures, well knownby those skilled in the art. For example, suppositories can be preparedby mixing the active ingredient with a conventional suppository basesuch as cocoa butter or other glycerides, e.g. Suppocire. in this case,the drug is mixed with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperature andwill therefore melt in the rectum to release the drug. Such materialsare cocoa butter and polyethylene glycols.

Generally, for compositions intended to be administered topically to theeye in the form of eye drops or eye ointments, the total amount of theinhibitor will be about 0.0001 to less than 4.0% (w/w).

Preferably, for topical ocular administration, the compositionsadministered according to the present invention will be formulated assolutions, suspensions, emulsions and other dosage forms. Aqueoussolutions are generally preferred, based on ease of formulation, as wellas a patient's ability to administer such compositions easily by meansof instilling one to two drops of the solutions in the affected eyes.However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds that are sparingly soluble inwater.

The compositions administered according to the present invention mayalso include various other ingredients, including, but not limited to,tonicity agents, buffers, surfactants, stabilizing polymer,preservatives, co-solvents and viscosity building agents. Preferredpharmaceutical compositions of the present invention include theinhibitor with a tonicity agent and a buffer. The pharmaceuticalcompositions of the present invention may further optionally include asurfactant and/or a palliative agent and/or a stabilizing polymer.

Various tonicity agents may be employed to adjust the tonicity of thecomposition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, simple sugars, such as dextrose,fructose, galactose, and/or simply polyols, such as the sugar alcoholsmannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, andhydrogenated starch hydrolysates may be added to the composition toapproximate physiological tonicity. Such an amount of tonicity agentwill vary, depending on the particular agent to be added. In general,however, the compositions will have a tonicity agent in an amountsufficient to cause the final composition to have an ophthalmicallyacceptable osmolality (generally about 150-450 mOsm, preferably 250-350mOsm and most preferably at approximately 290 mOsm). In general, thetonicity agents of the invention will present in the range of 2 to 5%w/w (e.g. 2 to 4% w/w). Preferred tonicity agents of the inventioninclude the simple sugars or the sugar alcohols, such as D-mannitol.

An appropriate buffer system (e.g. sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed.Preferably however, the buffer will be chosen to maintain a target pHwithin the range of pH 5 to 8, and more preferably to a target pH of pH5 to 7, or a target pH of 6.5 to 7.6.

Surfactants may optionally be employed to deliver higher concentrationsof inhibitor. The surfactants function to solubilise the inhibitor andstabilise colloid dispersion, such as micellar solution, microemulsion,emulsion and suspension. Examples of surfactants which may optionally beused include polysorbate, poloxamer, polyoxyl 40 stearate, polyoxylcastor oil, tyloxapol, triton, and sorbitan monolaurate. Preferredsurfactants to be employed in the invention have ahydrophile/lipophile/balance “HLB” in the range of 12.4 to 13.2 and areacceptable for ophthalmic use, such as TritonX114 and tyloxapol.

Additional agents that may be added to the ophthalmic compositions ofthe present invention are demulcents which function as a stabilisingpolymer. The stabilizing polymer should be an ionic/charged example withprecedence for topical ocular use, more specifically, a polymer thatcarries negative charge on its surface that can exhibit a zeta-potentialof (−)10-50 mV for physical stability and capable of making a dispersionin water (i.e. water soluble). A preferred stabilising polymer of theinvention would be polyelectrolyte, or polyelectrolytes if more thanone, from the family of cross-linked polyacrylates, such as carbomers,polycarbophil and Pemulen®, specifically Carbomer 974p (polyacrylicacid), at 0.1-0.5% w/w.

Other compounds may also be added to the ophthalmic compositions of thepresent invention to increase the viscosity of the carrier. Examples ofviscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily, vinyl polymers and acrylic acid polymers.

Topical ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1,or other agents known to those skilled in the art. Such preservativesare typically employed at a level of from 0.001 to 1.0% w/v. Unit dosecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

The medical practitioner, or other skilled person, will be able todetermine a suitable dosage for the compounds of the invention, andhence the amount of the compound of the invention that should beincluded in any particular pharmaceutical formulation (whether in unitdosage form or otherwise).

Embodiments of the invention that may be mentioned in connection withthe combination products described at (b) above include those in whichthe other therapeutic agent is one or more therapeutic agents that areknown by those skilled in the art to be suitable for treatinginflammatory diseases (e.g. the specific diseases mentioned below).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   steroids (e.g. budesonide, beclomethasone dipropionate,        fluticasone propionate, mometasone furoate, fluticasone furoate;        a further example is ciclesonide);    -   beta agonists, particularly beta2 agonists (e.g. terbutaline,        salbutamol, salmeterol, formoterol; further examples are        vilanterol, olodaterol, reproterol and fenoterol); and    -   xanthines (e.g. theophylline).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   muscarinic antagonists (e.g. tiotropium, umeclidinium,        glycopyrronium, aclidinium and daratropium, any of these for        example as the bromide salt); and    -   phosphodiesterase inhibitors.

Further, for the treatment of gastrointestinal disorders (such asCrohn's disease or ulcerative colitis), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   5-aminosalicylic acid, or a prodrug thereof (such as        sulfasalazine, olsalazine or balsalazide);    -   corticosteroids (e.g. prednisolone, methylprednisolone, or        budesonide);    -   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,        azathioprine or 6-mercaptopurine);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol or golimumab);    -   anti-IL12/IL23 antibodies (e.g. ustekinumab) or small molecule        IL12/IL23 inhibitors (e.g. apilimod);    -   anti-α4β7 antibodies (e.g. vedolizumab);    -   toll-like receptor (TLR) blockers (e.g. BL-7040; Avecia        (Cambridge, UK));    -   MAdCAM-1 blockers (e.g. PF-00547659);    -   antibodies against the cell adhesion molecule a4-integrin (e.g.        natalizumab);    -   antibodies against the IL2 receptor α subunit (e.g. daclizumab        or basiliximab);    -   anti-Smad7 antibodies (e.g. mongersen (GED0301;        all-P-ambo-2′-deoxy-P-thioguanylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thioguanyly-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-Pthiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thioadenylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxycytidine));    -   sphingosine 1-phosphate receptor 1 (S1P1) modulators (e.g.        ozanimod        ((S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile),        amiselimod (MT1303;        2-amino-2-{2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl}propane-1,3-diol)        or APD334        (2-[7-[4-cyclopentyl-3-(trifluoromethyl)benzyloxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3(R)-yl]acetic        acid));    -   JAK inhibitors (e.g. tofacitinib, baricitinib        (1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile),        filgotinib        (N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide),        peficitinib        (4-(((1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide),        upadacitinib        ((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide),        TD-1473 or R348 (see, for example, US 2014/0206708));    -   STAT3 inhibitors (e.g. TAK-114;        (3E)-1-methyl-3-(2-oxo-1H-indol-3-ylidene)indol-2-one);    -   receptor-interacting protein-1 (RIP1) kinase inhibitors (e.g.        GSK2982772);    -   Syk inhibitors and prodrugs thereof (e.g. fostamatinib and        R-406);    -   Phosphodiesterase-4 inhibitors (e.g. tetomilast);    -   HMPL-004;    -   probiotics;    -   microbiome modulators (e.g. SGM1019);    -   Dersalazine;    -   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071)        (e.g. for the treatment of gastrointestinal disorders (such as        Crohn's disease or ulcerative colitis), the other therapeutic        agent may be, for example, one or more agents selected from the        list comprising:    -   5-aminosalicylic acid, or a prodrug thereof (such as        sulfasalazine, olsalazine or balsalazide);    -   corticosteroids (e.g. prednisolone, methylprednisolone, or        budesonide);    -   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,        azathioprine or 6-mercaptopurine);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol or golimumab);    -   anti-IL12/IL23 antibodies (e.g. ustekinumab) or small molecule        IL12/IL23 inhibitors (e.g. apilimod);    -   anti-α4β7 antibodies (e.g. vedolizumab);    -   MAdCAM-1 blockers (e.g. PF-00547659);    -   antibodies against the cell adhesion molecule α4-integrin (e.g.        natalizumab);    -   antibodies against the IL2 receptor a subunit (e.g. daclizumab        or basiliximab);    -   JAK3 inhibitors (e.g. tofacitinib or R348);    -   Syk inhibitors and prodrugs thereof (e.g. fostamatinib and        R-406);    -   Phosphodiesterase-4 inhibitors (e.g. tetomilast);    -   HMPL-004;    -   probiotics;    -   Dersalazine;    -   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071)).

For the treatment of eye disorders (such as uveitis andkeratoconjunctivitis sicca (dry eye)), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   glucocorticoid agonists (e.g. mapracorat);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimurmab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   adenosine A3 receptor agonists (e.g. CF-101);    -   lifitegrast;    -   IL1 blockers (e.g. EBI-005; Hou et al. PNAS 2013, 110(10),        3913-3918);    -   RGN-259 (Thymosin 3β4);    -   SI-614;    -   OTX-101;    -   JNK inhibitors (e.g. XG-104);    -   MAP kinase signalling inhibitors (e.g. DA-6034;        {[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxochromen-7-yl]oxy}acetic        acid);    -   mucin stimulators (e.g. rebamipide;        2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoic        acid);    -   MIM-D3 (Tavilermide; see, for example, US 2013/0345395);    -   JAK inhibitors (e.g. tofacitinib, baricitinib        (1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile),        filgotinib        (N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide),        peficitinib        (4-(((1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide),        upadacitinib        ((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide),        TD-1473 or R348 (see, for example, US 2014/0206708)); and    -   protein kinase C inhibitors (e.g. AEB-071).        (e.g. for the treatment of eye disorders (such as uveitis and        keratoconjunctivitis sicca (dry eye)), the other therapeutic        agent may be, for example, one or more agents selected from the        list comprising:    -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   glucocorticoid agonists (e.g. mapracorat);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   adenosine A3 receptor agonists (e.g. CF-101);    -   lifitegrast;    -   JAK3 inhibitors (e.g. tofacitinib or R348); and    -   protein kinase C inhibitors (e.g. AEB-071)).

In particular embodiments, for the treatment of eye disorders (such asuveitis and keratoconjunctivitis sicca (dry eye)), the other therapeuticagent may be, for example, one or more agents selected from the listcomprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   JAK inhibitors (e.g. tofacitinib, baricitinib, filgotinib,        peficitinib, upadacitinib or R348) (e.g. JAK3 inhibitors such as        tofacitinib or R348); and    -   protein kinase C inhibitors (e.g. AEB-071).        Medical Uses

The compounds of the invention may be used as monotherapies forinflammatory diseases, or in combination therapies for such diseases.

Thus, embodiments of aspects (e) to (g) above that may be mentionedinclude those in which the compound of formula I, lx, Iy, Ia or Ib (orpharmaceutically acceptable salt thereof) is the sole pharmacologicallyactive ingredient utilised in the treatment.

However, in other embodiments of aspects (e) to (g) above, the compoundof formula I, Ix, Iy, Ia or Ib (or pharmaceutically acceptable saltthereof) is administered to a subject who is also administered one ormore other therapeutic agents (e.g. wherein the one or more othertherapeutic agents are as defined above in connection with combinationproducts).

When used herein, the term “inflammatory disease” specifically includesreferences to any one or more of the following:

-   (i) lung diseases or disorders having an inflammatory component,    such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis,    idiopathic pulmonary fibrosis or, particularly, COPD (including    chronic bronchitis and emphysema), asthma or paediatric asthma:-   (ii) skin diseases or disorders having an inflammatory component,    such as atopic dermatitis, allergic dermatitis, contact dermatitis    or psoriasis;-   (iii) nasal diseases or disorders having an inflammatory component,    such as allergic rhinitis, rhinitis or sinusitis;-   (iv) eye diseases or disorders having an inflammatory component,    such as conjunctivitis, allergic conjunctivitis, glaucoma, diabetic    retinopathy, macular oedema (including diabetic macular oedema),    central retinal vein occlusion (CRVO), dry and/or wet age related    macular degeneration (AMD), post-operative cataract inflammation,    or, particularly, keratoconjunctivitis sicca (dry eye, also known as    xerophthalmia), uveitis (including posterior, anterior and pan    uveitis), corneal graft and limbal cell transplant rejection; and-   (v) gastrointestinal diseases or disorders having an inflammatory    component, such as gluten sensitive enteropathy (coeliac disease),    eosinophilic esophagitis, intestinal graft versus host disease or,    particularly, Crohn's disease or ulcerative colitis.

References herein to diseases having an inflammatory component includereferences to diseases that involve inflammation, whether or not thereare other (non-inflammatory) symptoms or consequences of the disease.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I, which processcomprises:

-   (a) for compounds of formula I in which G represents    —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H, hydrolysis or hydrogenolysis of an    ester of formula I(P),

wherein R^(x) represents C₁₋₆ alkyl (e.g. methyl, ethyl or tert-butyl)or benzyl, respectively, and T, R⁴, R^(5a), R^(5b), A, Q, Z, n, r andHet¹ are as hereinbefore defined, for example under conditions known tothose skilled in the art, such as by basic hydrolysis with an alkalimetal hydroxide at room temperature in the presence of an aqueoussolvent system (e.g. a mixture of an aqueous solution, such as a 2 M to6 M solution, of NaOH with an alcohol such as methanol and a polaraprotic solvent such as THF);

-   (b) reaction of a compound of formula II,

with a compound of formula III,

wherein one of Z¹ and Z² is a structural fragment of formula IVa or IVb,

and the other of Z¹ and Z² is a structural fragment of formula V,

wherein W, V, R¹ to R⁴, R^(5a), R^(5b), A, Q, Z, G and n are ashereinbefore defined, for example under conditions known to thoseskilled in the art, for example at a temperature from ambient (e.g. 15to 30° C.) to about 110° C. in the presence of a suitable organicsolvent (e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, ormixtures thereof);

-   (c) reaction of a compound of formula IIa,

wherein Z¹ is as defined above, with a suitable azide-forming agent(i.e. a suitable source of a leaving group and activated azide ion, suchas diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30,2151-2157) under conditions known to those skilled in the art, such asat sub-ambient to ambient temperature (e.g. from an initial temperatureof about −5 to 5° C. to ambient temperature post-reaction) in thepresence of an amine base (e.g. triethylamine or a sterically hinderedbase such as N,N-diisopropylethylamine) and a suitable organic solvent(e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or mixturesthereof), which reaction is followed, without isolation, by thermalrearrangement (e.g. under heating) of the intermediate acyl azide (offormula Z¹—C(O)—N₃) e.g. at ambient temperature (such as from 15 to 30°C.) to provide, in situ, a compound of formula II, which compound isthen reacted with a compound of formula III, as defined above, toprovide the compound of formula I;

-   (d) reaction of a compound of formula IIb,

wherein LG¹ represents a suitable leaving group (e.g. imidazolyl,chloro, or aryloxy, such as phenoxy) and Z¹ is as defined above, with acompound of formula III, as defined above, for example under conditionsknown to those skilled in the art, such as at ambient temperature (e.g.from ambient to 80° C.), optionally in the presence of an amine base(e.g. triethylamine or a sterically hindered base likeN,N-diisopropylethylamine) and a suitable organic solvent (e.g. anaprotic solvent, such as dichloromethane, acetonitrile, tetrahydrofuranor an ester, such as isopropyl acetate);

-   (e) reaction of a compound of formula VI,

wherein LG² represents a suitable leaving group (e.g. a halo group suchas chloro or bromo) and T and A are as hereinbefore defined with acompound of formula VII,

wherein R⁴, R^(5a), R^(5b), Q, Z, G and n are as hereinbefore defined,for example under conditions known to those skilled in the art (e.g. asdescribed in J. Am. Chem. Soc. 2011, 133, 15686-15696), such as

-   -   for compounds of formula I in which A represents N, at elevated        temperature (e.g. from 50 to 110° C.) in the presence of a        suitable organic solvent (e.g. a polar aprotic solvent such as        DMF, THF, 1,4-dioxane, or mixtures thereof) and, optionally, an        acidic catalyst (e.g. a sulfonic acid such as        para-toluenesulfonic acid) or    -   for compounds of formula I in which A represents CH, at elevated        temperature (e.g. from 60 to 100° C.) in the presence of a        suitable organic solvent (e.g. a polar solvent such as DMF or        tert-butanol), a base (e.g. an inorganic base such as potassium        carbonate) and a suitable catalyst (e.g. a palladium(II)        catalyst such as BrettPhos G3 precatalyst        ([(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate);

-   (f) for compounds of formula I in which Q represents S(O)₁₋₂,    oxidation of a corresponding compound of formula I in which Q    represents S, for example under conditions known to those skilled in    the art (e.g. at 0 to 25° C. in the presence of a suitable solvent    (such as dichloromethane, methanol or a mixture thereof) and a    peracid, such as meta-chloroperbenzoic acid);

-   (g) for compounds of formula I in which Q represents C(O)NH,    reaction of a compound of formula VIII,

wherein LG³ represents OH, OR^(x) or a suitable leaving group (such ashalo) and T, A, R⁴ and R^(x) are as hereinbefore defined, with acompound of formula IX,

wherein R^(5a), R^(5b), Z, G and n are as hereinbefore defined, forexample under conditions known to those skilled in the art, such as

-   -   when LG³ represents OR^(x), reaction at ambient temperature in        the presence of a suitable Lewis acidic catalyst (e.g. a        trialkylaluminium reagent such as trimethylaluminium) and an        aprotic organic solvent (e.g. THF),    -   when LG³ represents OH, reaction in the presence of a tertiary        amine base (e.g., 4-dimethylaminopyridine, a trialkylamine such        as triethylamine or diisopropylethylamine or a cyclic amine such        as N-methylpyrrolidine or N-methylmorpholine), an amide        (peptide) coupling reagent (e.g. T3P, HATU, CDI, BOP, PyBOP,        HOAt, HOBt or a carbodiimide such as DCC or        diisopropylcarbodiimide) and an aprotic organic solvent (e.g. a        chlorinated solvent such as DCM, an ester such as ethyl acetate,        an amide of dimethylamine such as DMF, or a mixture of any such        solvents) or    -   when LG³ represents a leaving group such as halo, reaction in        the presence of a base (e.g. a tertiary amine base as mentioned        above) and an aprotic organic solvent (e.g. a chlorinated, ester        or amide solvent as mentioned above);

-   (h) for compounds of formula I in which G represents    —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H, oxidation of an alcohol of formula Xa,

wherein T, R⁴, R^(5a), R^(5b), A, Q, Z, n, r and Het¹ are ashereinbefore defined, for example under conditions known to thoseskilled in the art (see, for example,http://www.organic-chemistry.org/synthesis/C20/carboxylicacids/oxidationsalcohols.shtmand Tojo, G.; Fernandez, M. I. Oxidation of Primary Alcohols toCarboxylic Acids: A Guide to Current Common Practice, Springer-Verlag,New York, 2007), including reactions using the following oxidants

-   -   H₅IO₆ (e.g. in the presence of 1-2 mol % of a catalyst, such as        CrO₃ or pyridinium chlorochromate, and a solvent such as        acetonitrile, or a mixture of acetonitrile and water),    -   a peroxide, such as t-BuOOH (e.g. in the presence of a catalyst        such as bismuth(III) oxide), or    -   molecular oxygen or air (e.g. in the presence of: (i) a mixture        of a palladium(0) catalyst (e.g. Pd/C), a borohydride (e.g.        NaBH₄), an inorganic base (e.g. K₂CO₃ or KOH) and an aqueous        alcohol (e.g. ethanol or methanol); (ii) a silver N-heterocyclic        carbene catalyst (e.g. a bis(imidazol-2-ylidene) silver catalyst        such as a 1,3-bis[(6-bromopyridin-2-yl)methyl]imidazol-2-ylidene        silver catalyst) and a hydroxide base such as KOH or a        quaternary ammonium hydroxide (e.g. benzyltrimethylammonium        hydroxide); (iii) an organocatalyst such as        2-chloroanthraquinone and visible light irradiation; or (iv) one        or more catalysts (e.g. VO(acac)₂, Cu(II) 2-ethylhexanoate, or a        mixture thereof), a strong base (e.g. DABCO) and an ionic        liquid, such as a liquid based upon 1-butyl-3-methylimidazolium        trifluoromethanesulfonate), alternatively, oxidation of the        primary alcohol to the carboxylic acid may be carried out in        stepwise fashion, i.e., via the intermediate aldehyde, employing        one of the approaches outlined in Tojo, G.; Fernandez, M. I. In        Oxidation of Primary Alcohols to Carboxylic Acids: A Guide to        Current Common Practice, Springer-Verlag, New York, 2007,        Chapter 7, pp 105-110; or

-   (i) for compounds of formula I in which G represents —C(O)N(H)OH,    —C(O)N(H)OCH₃, —C(O)N(H)—S(O)₂CH₃ or —C(O)N(H)—S(O)₂N(CH₃)₂,    coupling of a corresponding compound of formula I in which G    represents —CO₂H with hydroxylamine, methoxyamine,    methanesulfonamide or dimethylsulfamide, respectively, under    conditions known to those skilled in the art (e.g. for coupling with    methanesulfonamide, reaction in the presence of a tertiary amine    base, an amide (peptide) coupling reagent and an aprotic organic    solvent, for example as described at (g) above);

-   (k) for compounds of formula I in which G represents a    hydroxy-substituted isoxazole having the structure:

reaction of a compound of formula Xb,

wherein T, A, R⁴, R^(5a), R^(5b), Q, Z, n and R^(x) are as hereinbeforedefined, with hydroxylamine, for example under conditions known to thoseskilled in the art (e.g. reaction at elevated temperature, such as atreflux, in the presence of a protic organic solvent, such as ethanol andoptionally in the presence of a suitable base, such as sodiumbicarbonate);

-   (l) for compounds of formula I in which G represents tetrazol-5-yl,    reaction of a compound of formula Xc,

wherein T, A, R⁴, R⁵, R^(5b), Q, Z, and n are as hereinbefore defined,with a suitable source of azide (e.g. azidotrimethylsilane), for exampleunder conditions known to those skilled in the art (e.g. reaction atelevated temperature in the presence of an aprotic organic solvent, suchas toluene and, optionally, a catalyst, such as dibutyltin oxide);

-   (m) for compounds of formula I in which G represents    5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, reaction of a compound of    formula Xc, as defined above, with hydroxylamine (e.g. under    conditions known to those skilled in the art, such as reaction at    elevated temperature in the presence of a protic solvent (e.g. EtOH    or water, or a mixture of the two)), followed by reaction of the    resulting N-hydroxyamidine (amidoxime) compound with a suitable    source of the —C(O)-moiety (e.g. a chloroformate, such as isobutyl    chloroformate, or phosgene, for example under conditions known to    those skilled in the art, such as at sub-ambient temperature in the    presence of an aprotic organic solvent (e.g. DMF) and a base (e.g.    pyridine));-   (n) deprotection of a protected derivative of a compound of formula    I, under conditions known to those skilled in the art, wherein the    protected derivative bears a protecting group on an O- or N-atom of    the compound of formula I (and, for the avoidance of doubt, a    protected derivative of one compound of formula I may or may not    represent another compound of formula I).

Examples of protected derivatives of compounds of formula I includethose where:

-   -   an O-atom is protected with a benzyl group, which benzyl group        may be removed by hydrogenation, for example in the presence of        a palladium catalyst (such as Pd/C);    -   an O-atom of an acid (e.g. a carboxylic, sulfonic, phosphonic or        phosphinic acid) is protected with an alkyl group (such as        methyl, ethyl or tert-butyl), which alkyl group may be removed        by either basic hydrolysis (e.g. for methyl or ethyl groups, by        a hydrolysis reaction using an alkali metal hydroxide such as        sodium hydroxide) or acid hydrolysis (e.g. for a tert-butyl        group, by a hydrolysis reaction using an acid such as        trifluoroacetic acid);    -   an N-atom of an amine is protected with a carbamate group, such        as a benzyl or tert-butyl carbamate, which groups may be removed        under similar conditions to those used to remove benzyl or        ter-butyl groups from O-atoms.

Protected derivatives of compounds of formula I include compounds offormula I(P).

In the processes described at (b) to (g) above, it may be desirable toprotect the C(O)₂H groups in the following compounds:

-   -   compounds of formula II, IIa or IIb in which Z¹ is a structural        fragment of formula V;    -   compounds of formula III in which Z² is a structural fragment of        formula V; or    -   compounds of formula VII or IX,        in which compounds G represents —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H.

When the C(O)₂H group in these compounds is protected, the protectinggroup may, for example, be an ester (e.g. wherein C(O)₂H is protected asan ester such as C(O)OR^(x), wherein R^(x) is as hereinbefore defined),which ester group may be removed according to procedures known to thoseskilled in the art (e.g. under conditions such as those described in (a)above).

Compounds of formula II, IIa, IIb, VI and VIII may be prepared accordingto or by analogy with methods known to those skilled in the art, forexample procedures outlined in WO 2014/162126 and WO 2015/092423.

Compounds of formula VII or Xc in which Q represents O or S may beprepared by reaction of a compound of formula X

wherein Q′ represents O or S, FG represents a real or latent NH₂ group(i.e. a group that is readily transformed into an NH₂ group, such asnitro or a protected variant NH-PG, where PG is a typical protectinggroup such as a carbamate ester or carboxamide; see, for example:Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis;Wiley, 4th revised edition, 2006: ISBN-10: 0471697540) and R⁴ is ashereinbefore defined, with a compound of formula XI (for the preparationof compounds of formula VII) or of formula XIa (for the preparation ofcompounds of formula Xc),

wherein LG⁴ represents a suitable leaving group (such asmethanesulfonate or halo), G′ represents —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂R^(y)or a carboxylic acid isostere (or protected variant thereof), and R^(y)represents H or R^(x), and R^(5a), R^(5b), Z, R^(x) and n are ashereinbefore defined, for example under conditions known to thoseskilled in the art, followed by:

-   (i) when FG represents NH-PG, removal of the PG protecting group,    -   when FG represents NO₂, reduction of NO₂ to NH₂ or    -   when FG represents C(O)O—(C₁₋₆ alkyl), saponification to provide        the corresponding carboxylic acid and then reaction with a        suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide; and/or-   (ii) when R^(y) represents R^(x), removal of the R^(x) group, for    example by hydrolysis (e.g. as described in respect of process (a)    above).

Compounds of formula IX, or protected derivatives thereof, may beprepared according to or by analogy with methods known to those skilledin the art, for example procedures outlined in WO 2011/037610.

Compounds of formula Xb may be prepared by reaction of a correspondingcompound of formula I in which G represents —CO₂H with2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) under (peptide)coupling conditions known to those skilled in the art (e.g. reaction inthe presence of a tertiary amine base, an amide (peptide) couplingreagent and an aprotic organic solvent, for example as described at (g)above), followed by thermal degradation (causing loss of one equivalentof acetone and one equivalent of CO₂) of the resulting product (anacylated form of Meldrum's acid).

Compounds of formula XI may be prepared by reaction of a compound offormula XII,

wherein R^(y1) represents H or a protecting group (e.g. benzyl) and n isas hereinbefore defined, with either a compound of formula XIIIa.

wherein LG⁵ represents a suitable leaving group (such asmethanesulfonate or halo) and R^(5a), R^(5b) and G′ are as hereinbeforedefined or, for compounds of formula XI in which R^(5a) represents H andG′ represents a carboxylic acid isostere (or protected variant thereof)or —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂R^(x), with a compound of formula XIIIb,

wherein G″ represents a carboxylic acid isostere (or protected variantthereof) or —[(CH₂)_(r)Het¹]₀₋₁-C(O)₂R^(x), R^(5b) and R^(x) are ashereinbefore defined, in either case under conditions such as thoseknown to persons skilled in the art, followed by conversion of theR^(y1)O— group to a LG⁴ group, for example, when R^(y1) represents aprotecting group, by removal of that protecting group (e.g. underconditions known to those skilled in the art) followed by the use ofreagents (e.g. for compounds of formula XII in which LG⁴ ismethanesulfonate, a reagent such as methanesulfonyl chloride) andconditions known to those skilled in the art.

It will be understood by persons skilled in the art that compoundsrepresented by formulae II, IIx and IIb are generally reactiveintermediates. These intermediates may be formed in situ and reacteddirectly, without isolation, with compounds of formula III to providecompounds of formula I. Furthermore, it will be understood by thoseskilled in the art that the use of appropriate protective groups may berequired during the processes described above for any of the groups Z¹and Z² which possess chemically-sensitive functional groups, forexample, a hydroxyl group or an amino function.

Compounds illustrated above (e.g. intermediates such as compounds offormulae IX, XIa, XII, XIIIa and XIIIb) are either commerciallyavailable, or can be obtained using the cited procedures, or can bereadily prepared by conventional methods by those skilled in the art.See, for example, Regan, J. et al.; J. Med. Chem. 2003, 46, 4676-4686,WO 2000/043384, WO 2007/053346, WO 2007/087448, WO 2007/089512, WO2009/117080, WO 2013/050756, WO 2014/027209, WO 2014/033446, WO2014/033447, WO 2014/033449, WO 2014/076484, WO 2014/140582 WO2014/162121, WO 2014/162126, WO 2015/092423, WO 2016/051187, WO2016/051188, Lassalas et al., J. Med. Chem. (2016), 59, 3183-3203,Ballatore et al., Chem. Med. Chem. (2013), 8(3), 385-395 and Boyd etal., Bioorg. Med. Chem. Lett. (2015), 25, 1990-1994.

Compounds of formulae Ia, Ix, Iy, Ib and Ic may be prepared by methodsanalogous to those described above, such as methods in which theabove-mentioned intermediates are, where necessary, replaced bycompounds having appropriately modified substituent definitions. Forexample, for the synthesis of compounds of formula Ix or Iy, thefollowing intermediates may be used (wherein R¹ to R⁴, R^(5a), R^(5b),R^(x), A, Q, n, LG² and LG³ are as hereinbefore defined).

Original Replacement formula I(P) For synthesis of formula lx:

Ix(P) For synthesis of formula Ix:

Iy(P) formula V For synthesis of formula Ix:

Vx For synthesis of formula Iy:

Vy formula VI For synthesis of formula Ix:

VIx For synthesis of formula Iy:

VIy formula VII For synthesis of formula Ix:

VIIx For synthesis of formula Iy:

VIIy formula VIII For synthesis of formula Ix:

VIIIx For synthesis of formula Iy: not applicable formula IX Forsynthesis of formula Ix:

IXx For synthesis of formula Iy: not applicable formula Xa For synthesisof formula Ix:

Xax For synthesis of formula Iy:

Xay formula XI For synthesis of formula Ix:

XIx For synthesis of formula Iy:

XIy formula XIIIa For synthesis of formula Ix:

XIIIax For synthesis of formula Iy:

XIIIay formula XIIIb For synthesis of formula Ix:

XIIIbx For synthesis of formula Iy:

XIIIby

Novel intermediates as described herein form an aspect of the invention.In this respect, further aspects of the invention relate to:

-   (i) a compound of formula I(P), Ix(P) or Iy(P) as hereinbefore    defined, or a salt or protected derivative thereof;-   (ii) a compound of formula II, IIa or IIb as hereinbefore defined,    wherein Z¹ represents a structural fragment of formula V, Vx or Vy,    or a salt or protected derivative thereof;-   (iii) a compound of formula III as hereinbefore defined, wherein Z²    represents a structural fragment of formula V, Vx or Vy, or a salt    or protected derivative thereof; and-   (iii) a compound of formula VII, VIIx or VIIy as hereinbefore    defined, or a salt or protected derivative thereof.

In these aspects of the invention, embodiments of the compounds offormulae I(P), Ix(P), II, IIa, IIb, III, VII and VIIx that may bementioned include those in which one or more (e.g. all) of the followingapply:

-   (a) R⁴ represents methoxy, optionally substituted by one or more    (e.g. two or three) halo (e.g. fluoro) substituents or,    particularly, R⁴ represents methoxy;-   (b) R^(5a) and R^(5b) both represent H;-   (c) Q represents C(O)NH, S, S(O), S(O)₂ or, particularly, O;-   (d) Z represents O;-   (e) n represents 1, 2 or 3 (e.g. 3 or, particularly, 2);-   (f) for compounds of formulae I(P), II, IIa, IIb and III, A    represents N or, particularly, CH.

Further embodiments of the compounds of formula I(P) or Ix(P) that maybe mentioned include those in which one or more (e.g. all) of thefollowing apply:

-   (a) R¹ represents methoxy;-   (b) R² represents —C(O)NH₂, —C(O)NHCH₃, —S(O)₁₋₂CH₃, —P(O)(CH₃)₂,    —N(CH₃)S(O)₂CH₃, or —NHS(O)₂CH₃;-   (c) R³ represents trimethylsilyl or tert-butyl;-   (d) A represents CH or N;-   (e) R⁴ represents methoxy, optionally substituted by one or more    halo substituents;-   (f) R^(5a) and R^(5b) both represent H;-   (g) Q represents C(O)NH, S, S(O), S(O)₂ or O;-   (h) Z represents O;-   (i) n represents 1, 2 or 3.

In any of such embodiments, as well as in respect of embodiments ofcompounds of formula Iy(P), R^(x) may represent C₁₋₆ alkyl or benzyl.

Still further embodiments of the compounds of formula I(P) or Ix(P) thatmay be mentioned include those in which one or more (e.g. all) of thefollowing apply:

-   (a) R¹ represents methoxy;-   (b) R² represents —NHS(O)₂CH₃;-   (c) R³ represents tert-butyl;-   (d) A represents CH;-   (e) R⁴ represents methoxy;-   (f) R^(5a) and R^(5b) both represent H;-   (g) Q represents O;-   (h) Z represents O;-   (i) n represents 2.

In any of such embodiments, as well as in respect of embodiments ofcompounds of formula Iy(P), R^(x) may represent ethyl.

Particular embodiments of the compounds of formulae II, IIa, IIb and IIIinclude those in which:

-   A represents OH;-   R⁴ represents methoxy;-   R^(5a) and R^(5b) both represent H;-   Q represents O;-   Z represents O; and-   n represents 2.

Protected derivatives of the compounds of formulae III, VII, VIIx andVIIy include those in which the essential NH₂ group is protected. Inthis respect, such protected derivatives include amides or,particularly, carbamates of those compounds. For example, thoseprotected derivatives include compounds in which the NH₂ group isreplaced by FG (as defined above, except that it does not represent NH₂(e.g. FG represents nitro)) or, particularly a H-atom of the NH₂ groupis replaced by:

-   -   R′—C(O)—, wherein R′ is C₁₋₈ alkyl substituted by one or more        fluoro groups or R′ is H, C₁₋₈ alkyl, phenyl or benzyl, which        latter two groups are optionally substituted by one or more        groups selected from halo, hydroxy, methyl and methoxy; or    -   R″—O—C(O)—, wherein R″ is tert-butyl, phenyl, benzyl or        fluorenyl, which latter three groups are optionally substituted        by one or more groups selected from halo, hydroxy, methyl and        methoxy.

For the compounds of formulae II, IIa, IIb, III, VII in which Grepresents —[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H, and for compounds of formulaeVIIx and VIIy, protected derivatives of those compounds additionally (oralternatively) include those in which the carboxyl moiety is protected.In this respect, such protected derivatives also include esters (e.g.wherein C(O)₂H is protected as an ester such as C(O)OR^(x), whereinR^(x) is as hereinbefore defined) of such compounds.

Particular embodiments of the compounds of formula I(P) or Ix(P) thatmay be mentioned include:

-   methyl    2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)acetate;-   ethyl    2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate;    and-   ethyl    2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate,    or a salt thereof.

The aspects of the invention described herein (e.g. the above-mentionedcompounds, combinations, methods and uses) may have the advantage that,in the treatment of the conditions described herein, they may be moreconvenient for the physician and/or patient than, be more efficaciousthan, be less toxic than, have better selectivity over, have a broaderrange of activity than, be more potent than, produce fewer side effectsthan, have a better pharmacokinetic and/or pharmacodynamic profile than,have more suitable solid state morphology than, have better long termstability than, or may have other useful pharmacological propertiesover, similar compounds, combinations, methods (treatments) or usesknown in the prior art for use in the treatment of those conditions orotherwise.

The compounds of the invention may additionally (or alternatively):

-   -   exhibit a long duration of action and/or persistence of action        (e.g. in comparison to other previously disclosed p38 MAP kinase        inhibitors such as, for example, BIRB796);    -   exhibit potent inhibition of Syk (e.g. they may have an IC₅₀        against Syk of 500 nM or less, such as 350 nM or less);    -   not strongly inhibit GSK 3α (e.g. they may have an IC₅₀ against        GSK 3α of 1,000 nM or greater; such as 1,500, 2,000, 3,000,        4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 nM or        greater);    -   target a smaller portion of the kinome, i.e., with improved        selectivity, as illustrated by lowered KinomeScan Selectivity        Scores;    -   maintain a relatively high local drug concentration between        doses (e.g. a high local concentration relative to other        previously disclosed p38 MAP kinase inhibitors such as, for        example, BIRB796);    -   exhibit properties that are particularly suited to topical/local        administration (e.g. following topicalilocal administration, the        generation of high target tissue concentrations but low plasma        concentrations of the compounds of formula (I) and/or rapid        clearance of the compounds of formula (I) from plasma, for        example as a result of high renal or hepatic extraction);    -   exhibit little or no β-catenin induction and/or inhibition of        mitosis in cells;    -   display reduced cytotoxicities;    -   not produce increases in binucleated cells containing        micronuclei in the human lymphocyte in vitro micronucleus test;    -   exhibit little or no time-dependent inhibition of members of the        cytochrome P450 superfamily;    -   show improved chemical stability in the presence of water (e.g.        stability to hydrolysis in aqueous mixtures at elevated        temperatures) compared to previously disclosed p38 MAP kinase        inhibitors such as, for example, BIRB796;    -   following administration to a patient, give rise to metabolites        associated with little or no safety (e.g. toxicity) concerns;    -   display reduced ocular irritancy or toxicity in both preclinical        species and humans following topical administration;    -   exhibit good aqueous solubility and/or cellular permeability        (e.g. exhibit good aqueous solubility and potent inhibition of        the release of certain cytokines, such as IL-8 and/or IFNγ, in        cells), for example relative to Reference Compound A,        (3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-propanoic        acid, and/or Reference Compound B,        3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;    -   give rise to a faster dissolution rate in intestinal or colonic        fluids, for example relative to Reference Compound A and/or        Reference Compound B;    -   be more readily formulated in aqueous solution in the pH range        7-8 with lower quantities of solubilising excipients;    -   have a high degree of crystallinity; and/or    -   exhibit little or no hygroscopicity in the solid state.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows comparative XRPD profiles for two samples of2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid, sodium salt, produced either by Method 1 (upper trace, with peaksas described in Table A below) or Method 2 (lower trace, with peaks asdescribed in Table B below) of Example 31 below.

TABLE A peak listing for XRPD profile of product of Example 31, Method 1Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%]3.9317 997.91 0.1023 22.47367 68.42 4.4389 376.68 0.1279 19.90685 25.835.9292 224.18 0.1279 14.90639 15.37 8.9406 240.27 0.1535 9.89115 16.479.4882 279.74 0.1023 9.32147 19.18 11.2243 804.76 0.1279 7.88327 55.1714.6967 1458.55 0.2303 6.02757 100.00 15.8103 156.22 0.1535 5.6054610.71 18.0348 732.39 0.1791 4.91876 50.21 18.4303 539.12 0.1023 4.8140836.96 18.9396 749.55 0.3582 4.68577 51.39 21.0357 301.56 0.1535 4.2233420.68 22.6909 254.38 0.1535 3.91888 17.44 26.2933 130.65 0.1279 3.389568.96 27.5888 51.44 0.4093 3.23328 3.53 27.9150 40.67 0.1279 3.19623 2.7928.9822 37.73 0.3070 3.08092 2.59 33.3548 18.18 0.1535 2.68635 1.25

TABLE B peak listing for XRPD profile of product of Example 31, Method 2Pos. Height FWHM d-spacing Rel. Int. [°2Th.] [cts] [°2Th.] [Å] [%]3.9435 937.49 0.1023 22.40637 92.78 4.4734 508.47 0.2047 19.75372 50.325.8834 347.72 0.2558 15.02234 34.41 9.0053 212.93 0.1791 9.82024 21.079.5071 332.04 0.1535 9.30301 32.86 11.3151 633.79 0.2047 7.82025 62.7214.7734 1010.46 0.2558 5.99645 100.00 15.6873 215.33 0.5117 5.6491421.31 18.0549 555.83 0.2558 4.91331 55.01 19.0099 725.20 0.3582 4.6685871.77 21.1976 433.24 0.8187 4.19144 42.88 22.7798 354.68 0.4093 3.9037835.10 26.3822 80.59 0.3070 3.37834 7.98 27.6970 45.38 0.6140 3.220894.49 31.6934 43.32 0.8187 2.82328 4.29

FIG. 2 shows the heat flow traces obtained by DSC analysis of twosamples of2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid, sodium salt, produced either by Method 1 (upper line) or Method 2(lower line) of Example 31 below.

EXPERIMENTAL METHODS

General Procedures

All starting materials and solvents were obtained either from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations wereperformed on a Thales H-cube flow reactor under the conditions stated orunder a balloon of hydrogen. Microwave reactions were performed in a CEMDiscover and Smithcreator microwave reactor, heating to a constanttemperature using variable power microwave irradiation.

Normal phase column chromatography was routinely carried out on anautomated flash chromatography system such as CombiFlash Companion orCombiFlash RF system using pre-packed silica (230-400 mesh, 40-63 μm)cartridges. SCX was purchased from Supelco and treated with 1Mhydrochloric acid prior to use. Unless stated otherwise the reactionmixture to be purified was first diluted with MeOH and made acidic witha few drops of AcOH. This solution was loaded directly onto the SCX andwashed with MeOH. The desired material was then eluted by washing with1% NH₃ in MeOH.

Analytical Methods

Analytical HPLC was carried out using a Waters Xselect CSH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of 0.1% Formic Acid in MeCN in0.1% aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 μm, 4.6×30 mmcolumn eluting with a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. UV spectra of the eluted peaks were measured using either adiode array or variable wavelength detector on an Agilent 1100 system.

Analytical LCMS was carried out using a Waters Xselect CSH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of 0.1% Formic Acid in MeCN in0.1% aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 μm, 4.6×30 mmcolumn eluting with a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. UV and mass spectra of the eluted peaks were measured usinga variable wavelength detector on either an Agilent 1200 or an AgilentInfinity 1260 LCMS with 6120 single quadrupole mass spectrometer withpositive and negative ion electrospray.

Preparative HPLC was carried out using a Waters Xselect CSH C18, 5 μm,19×50 mm column using either a gradient of either 0.1% Formic Acid inMeCN in 0.1% aqueous Formic Acid or a gradient of MeCN in aqueous 10 mMAmmonium Bicarbonate or employing a Waters Xbridge BEH C18, 5 μm, 19×50mm column using a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. Fractions were collected following detection by UV at asingle wavelength measured by a variable wavelength detector on a Gilson215 preparative HPLC or Varian PrepStar preparative HPLC or by mass andUV at a single wavelength measured by a ZQ single quadrupole massspectrometer, with positive and negative ion electrospray, and a dualwavelength detector on a Waters FractionLynx LCMS.

¹H NMR Spectroscopy: ¹H NMR spectra were acquired on a Bruker Avance IIIspectrometer at 400 MHz. Either the central peaks of chloroform-d,dirmethylsulfoxide-d₆ or an internal standard of tetramethylsilane wereused as references.

Preparation of Compounds of the Invention

Example 12-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)aceticacid, hydrochloride salt

(i) Methyl 3-amino-5-methoxybenzoate

To a stirred suspension of 3-amino-5-methoxybenzoic acid (47 g, 281mmol) in MeOH (1 L) at 0° C. was added thionyl chloride (123 mL, 1687mmol) dropwise. The reaction was warmed to rt and stirred for 72 h. Theresulting solid was isolated by filtration, washing with diisopropylether, affording the product as the HCl salt. The filtrate wasevaporated, the residue triturated with MeOH/ether, filtered and washedwith ether. The combined solid was suspended in DCM (500 mL) andbasified with sat. aq. NaHCO₃ solution (300 mL) with vigorous stirring.The organic phase was separated, washed with brine (200 mL), dried(MgSO₄), filtered and evaporated under reduced pressure to give a solid.The solid was triturated with ether/isohexane to afford the sub-titlecompound (46 g) as a solid.

¹H NMR (400 MHz, DMSO-d6) δ: 6.83 (dd, 1H), 6.63 (dd, 1H), 6.37 (t, 1H),5.42 (s, 2H), 3.79 (s, 3H), 3.70 (s, 3H).

LCMS m/z 182 (M+H)⁺ (ES⁺)

(ii) Methyl 3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzoate

A mixture of the product from step (i) above (10.8 g, 59.6 mmol),tert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see,for example, WO 2014/162126; 20 g, 53.9 mmol), finely ground potassiumcarbonate (15.2 g, 110 mmol) and BrettPhos G3 precatalyst (800 mg, 0.883mmol) in tBuOH (400 mL) was extensively degassed with N₂. The reactionwas heated under nitrogen at 90° C. (block temperature) for 2 h. Thereaction mixture was diluted with DCM (500 mL), filtered through Celiteand concentrated in vacuo to afford a brown foam. The foam wastriturated with Et₂O (500 mL). The resultant solid was filtered, washingwith further Et₂O (100 mL), and dried in vacuo to affording thesub-title compound (25.6 g) as an off-white/pale-grey solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.37 (s, 1H), 9.19 (s, 1H), 8.13-8.14 (m,2H), 7.84 (d, 1H), 7.77 (bs, 1H), 7.69 (t, 1H), 7.55-7.65 (m, 3H), 7.36(d, 1H), 6.96 (bs, 1H), 6.62 (dd, 1H), 6.09 (d, 1H), 3.82 (s, 3H), 3.75(s, 3H), 1.53 (s, 9H).

LCMS m/z 516 (M+H)⁺ (ES⁺)

(iii) Methyl3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzoate

HCl (5 N in iPrOH) (79 mL, 395 mmol) was added to a solution of theproduct from step (ii) above (20 g, 38.8 mmol) in DCM (250 mL) and thereaction left stirring overnight. Et₂O (300 mL) was added and theresulting precipitate was isolated by filtration, washing with furtherEt₂O. The solid was partitioned between DCM (400 mL) and sat. aq. NaHCO₃solution (600 mL). The organic layer was dried via hydrophobic frit andconcentrated in vacuo to afford the sub-title compound (15.5 g) as abeige foam.

¹H NMR (400 MHz, DMSO-d6) δ: 9.09 (s, 1H), 8.15-8.18 (m, 1H), 8.08 (d,1H), 7.75 (t, 1H), 7.69 (t, 1H), 7.63-7.65 (m, 1H), 7.43-7.47 (m, 2H),7.11 (d, 1H), 6.95 (t, 1H), 6.72 (d, 1H), 6.56 (dd, 1H), 6.04 (d, 1H),5.83 (bs, 2H), 3.82 (s, 3H), 3.75 (s, 3H).

LCMS m/z 416 (M+H)⁺ (ES⁺)

(iv) Methyl3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzoate

Triethylamine (28 μL, 0.201 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (see,for example, WO 2014/162126; 480 mg, 1.223 mmol) and the product fromstep (iii) above (412 mg, 0.992 mmol) in iPrOAc (15 mL) at 60° C. (blocktemperature) and the mixture stirred for 24 h. The solution was cooledto rt and concentrated in vacuo affording a red oil. The crude productwas purified by chromatography on the Companion (40 g column, 1-5% MeOHin DCM) to afford the sub-title compound (580 mg) as a pale pink foam.

LCMS m/z 714 (M+H)⁺ (ES⁺)

(v)3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamidophenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzoicacid, hydrochloride salt

To a stirred solution of the product from step (iv) above (580 mg, 0.813mmol) in THF (20 mL) was added NaOH (6M aq.) (2 mL, 12.00 mmol). MeOH (5mL) was added and the reaction stirred overnight. The reaction wasconcentrated in vacuo affording a yellow solid. The solid was suspendedin 1 M HCl (20 mL) and the resulting gel-like solid filtered, washingwith water. The resulting solid was dried for 1 h on the frit thenfurther dried at 40° C. under vacuum affording the sub-title compound(526 mg) as an off-white solid.

LCMS m/z 699.77 (M+H)⁺ (ES⁺)

(vi) Methyl 2-(2-(2-aminoethoxy)ethoxy)acetate, trifluoroacetic acidsalt

To a stirred solution of methyl2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oate (see, forexample, WO 2011/037610; 195 mg, 0.703 mmol) in DCM (2 mL) was added TFA(500 μL, 6.49 mmol) and the mixture stirred at rt for 1 h. The reactionwas concentrated in vacuo then re-concentrated from toluene affordingthe sub-title compound (230 mg) as a colourless oil.

LCMS m/z 178 (M+H)⁺ (ES⁺)

(vii) Methyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-amino)-5-methoxybenzamido)ethoxy)ethoxy)acetate

HATU (120 mg, 0.316 mmol) was added to a stirred solution of the productfrom step (v) above (150 mg, 0.204 mmol), the product from step (vi)above (100 mg, 0.343 mmol) and Hünig's Base (250 μL, 1.431 mmol) in NMP(2 mL) at rt. The mixture was stirred for 2 h. The reaction waspartitioned between water (15 mL) and EtOAc (10 mL). The aqueous phasewas extracted with EtOAc (5 mL) and the combined organics washed withwater and brine, then dried via hydrophobic frit and concentrated invacuo. The crude product was purified by chromatography on the Companion(12 g column, 1-5% MeOH in DCM) to afford the sub-title compound (173mg) as a colourless gum.

LCMS m/z 859 (M+H)⁺ (ES⁺)

(viii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)aceticacid, hydrochloride salt

To a stirred solution of the product from step (vii) above (173 mg,0.201 mmol) in THF (3 mL) was added NaOH (6 M aq.) (0.30 mL, 1.800mmol). MeOH (1 mL) was added and the resulting solution stirred at rtfor 2 h. The reaction was concentrated in vacuo affording a yellowsolid. The solid was suspended in 1M HCl (10 mL) and the mixturesonicated. The resulting suspension was filtered and the recovered solidwashed with water then dried in vacuo at 40° C. overnight affording thetitle compound (140 mg) as a colourless solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.61 (bs, 1H), 9.53 (s, 1H), 9.15 (s, 1H),8.99 (s, 1H), 8.46 (t, 1H), 8.35 (d, 1H), 8.18 (d, 1H), 8.15 (d, 1H),8.07 (d, 1H), 7.87 (d, 1H), 7.71-7.74 (m, 1H), 7.62-7.66 (m, 1H),7.43-7.45 (m, 2H), 7.35 (s, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 6.73 (bs,1H), 6.22 (s, 1H), 4.01 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.51-3.60(m, 6H), 3.40 (q, 2H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 845 (M+H)⁺ (ES⁺)

Example 22-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) Ethyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate

A solution of ethyl diazoacetate (1.9 mL, 18.32 mmol) in DCM (20 mL) wasadded dropwise to a solution of diethylene glycol (5.0 mL, 52.7 mmol)and rhodium(II) acetate dimer (160 mg, 0.362 mmol) in DCM (300 mL) over1 h. The reaction was stirred at rt overnight. The mixture wasevaporated under reduced pressure and the residue purified bychromatography on silica gel (220 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (2.38 g) as a dark blue oil.

¹H NMR (400 MHz, CDCl₃) δ: 4.23 (q, 2H), 4.19 (s, 2H), 3.60-4.05 (m,8H), 1.28 (t, 3H).

(ii) Ethyl 2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)acetate

Methanesulfonyl chloride (0.6 mL, 7.70 mmol) was added dropwise to asolution of the product from step (i) above (1.20 g, 6.24 mmol) and Et₃N(1.7 mL, 12.20 mmol) in DCM (20 mL) at 0-5° C., warmed to rt and stirredfor 2 h. The mixture was partitioned between DCM (50 mL) and water (30mL), the organic layer washed with sat. aq. NaHCO₃ (30 mL), dried(MgSO₄), filtered and evaporated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (40 g column, 0-70%EtOAc/isohexane) to afford the sub-title compound (1.494 g) as an oil.

¹H NMR (400 MHz; CDCl₃) δ 4.42-4.39 (m, 2H), 4.24 (q, 2H), 4.15 (s, 2H),3.82-3.79 (m, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 1.31 (t, 3H).

(iii) Ethyl 2-(2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethoxy)acetate

A mixture of 3-methoxy-5-nitrophenol (1.973 g, 11.67 mmol), the productfrom step (ii) above (2.92 g, 10.80 mmol) and K₂CO₃ (4.48 g, 32.4 mmol)in DMF (60 mL) was heated at 60° C. for 20 h. The reaction was cooled tort then partitioned between ether (200 mL) and water (200 mL). Theorganic layer was washed with sat. aq. NaHCO₃ solution (100 mL) andbrine (100 mL) then dried (MgSO₄), filtered and evaporated under reducedpressure. The crude product was purified by chromatography on silica gel(80 g column, 0-50% EtOAc/isohexane) to afford the sub-title compound(3.35 g) as a yellow oil.

LCMS m/z 344 (M+H)⁺ (ES⁺)

(iv) Ethyl 2-(2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethoxy)acetate

To a solution of the product from step (iii) above (3.35 g, 9.76 mmol)in EtOH (20 mL) and EtOAc (5 mL) was added Pd/C (5 wt %) (0.5 g, 0.235mmol). The resulting suspension was stirred under a 5 bar (0.5 MPa)atmosphere of H₂ for 8 h. The reaction was purged with N₂ then filteredthrough Celite. The filtrate was concentrated in vacuo affording thesub-title compound (3.0 g) as a pale yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ: 5.75 (d, 2H), 5.68 (t, 1H), 5.06 (s, 2H),4.13 (s, 2H), 4.12 (q, 2H), 3.93-3.96 (m, 2H), 3.68-3.70 (m, 2H),3.58-3.64 (m, 4H), 3.62 (s, 3H), 1.20 (s, 3H).

LCMS m/z 314 (M+H)⁺ (ES⁺)

(v) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see, for example, WO 2014/162126; 300 mg, 0.526 mmol), the product fromstep (iv) above (247 mg, 0.789 mmol) and pTSA hydrate (30 mg, 0.158mmol) in THF (5 mL) was heated at 65° C. for 40 h. The mixture wascooled, partitioned between EtOAc (100 mL) and sat. aq. NaHCO₃ (50 mL),the organic layer washed with 1 M HCl (50 mL), water (50 mL), dried(MgSO₄), filtered and evaporated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (40 g column, 0-5%MeOH/DCM) to afford the sub-title compound (378 mg) as a foam.

LCMS m/z 847 (M+H)⁺ (ES⁺)

(vi) 2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-methylsulfonamidophenyl)ureido)-naphthalen-1-oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

A mixture of the product from step (v) above (376 mg, 0.444 mmol) and 2M aq. NaOH (700 μL, 1.400 mmol) in THF (5 mL) and MeOH (2 mL) wasstirred at rt for 20 h. The solvent was removed in vacuo, the residuedissolved in water (5 mL) and acidified with AcOH. The mixture wasevaporated and the residue purified by chromatography on the Companion(RP Flash C18) (40 g column, 15-75% MeCN/10 mM Ammonium Bicarbonate) toafford the title compound (72 mg) as a white solid.

¹H NMR (400 MHz; DMSO-d6) δ 12.57 (s, 1H), 9.43 (s, 1H), 9.37 (s, 1H),9.15 (s, 1H), 8.94 (s, 1H), 8.42 (d, 1H), 8.28 (d, 1H), 8.19 (d, 1H),8.11 (d, 1H), 7.85 (d, 1H), 7.70-7.65 (m, 1H), 7.61-7.56 (m, 1H), 7.42(d, 1H), 7.02 (d, 1H), 6.80 (brs, 2H), 6.54 (d, 1H), 6.04 (s, 1H), 4.00(s, 2H), 3.89-3.83 (m, 2H), 3.81 (s, 3H), 3.69-3.64 (m, 2H), 3.60-3.54(m, 4H), 3.51 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 819 (M+H)⁺ (ES⁺)

Example 32-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy)-3-(methylsulfonamido)phenyl)ureido-naphthalen-1-yl)oxy)pyridin-2-yl)amino-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

Method 1

(i) Ethyl2-(2-(2-(3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)-amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, WO 2014/162126; 497 mg, 1.340 mmol), ethyl2-(2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethoxy)acetate (see Example2(iv) above; 420 mg, 1.340 mmol) and K₂CO₃ (556 mg, 4.02 mmol) in DMF (6mL) was degassed under vacuum, back-filling with N₂ three times.BrettPhos G3 precatalyst (37 mg, 0.041 mmol) was added and the mixtureheated to 80° C. for 1 h. The mixture was cooled to rt and partitionedbetween EtOAc (70 mL) and water (50 mL). The organic layer washed withwater (50 mL) and brine (30 mL) then dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (40 g column, 0-100% EtOAc/isohexane) to afford thesub-title compound (870 mg) as a colourless foam.

LCMS m/z 648 (M+H)⁺ (ES⁺)

(ii) Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-phenoxy)ethoxy)ethoxy)acetate

A mixture of the product from step (i) above (690 mg, 1.065 mmol) andTFA (1 mL, 12.98 mmol) in DCM (5 mL) was stirred at rt for 20 h thenevaporated. The residue was partitioned between EtOAc (60 mL) and sat.aq. NaHCO₃ solution (40 mL), the organic layer was separated, washedwith water (40 mL), dried (MgSO₄), filtered and evaporated under reducedpressure to afford the sub-title compound (572 mg) as a brown gum.

LCMS m/z 548 (M+H)⁺ (ES⁺)

(iii) Ethyl2-(2-(2-(3-((4-((4-(3-(tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxyacetate

A mixture of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (see,for example, WO 2014/162126; 490 mg, 1.249 mmol), the product from step(ii) above (570 mg, 1.041 mmol) and Et₃N (50 μL, 0.359 mmol) in THF (10mL) was heated under reflux for 24 h. The solvent was removed and theresidue purified by chromatography on silica gel (40 g column, 0-5%MeOH/DCM) to afford the sub-title compound (736 mg) as a foam.

LCMS m/z 844 (M+H)⁺ (ES⁺)

(iv)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureidonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

A mixture of the product from step (iii) above (803 mg, 0.892 mmol) andaq. 2 M NaOH (1.3 mL, 2.60 mmol) in THF (8 mL) and MeOH (3 mL) wasstirred at rt for 20 h. The reaction was acidified with AcOH (3 mL) thenconcentrated in vacuo affording a pale solid. The residue was purifiedby chromatography on the Companion (RP Flash C18) (40 g column, 15-75%MeCN/10 mM Ammonium Bicarbonate) to afford the title compound (653 mg)as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H),8.32 (d, 1H), 8.19 (d, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 7.86 (d, 1H),7.67-7.71 (m, 1H), 7.58-7.62 (m, 1H), 7.38 (d, 1H), 7.03 (d, 1H), 6.86(s, 1H), 6.78 (s, 1H), 6.59 (dd, 1H), 6.09 (d, 1H), 6.03 (t, 1H),3.93-3.96 (m, 2H), 3.93 (s, 2H), 3.81 (s, 3H), 3.69-3.71 (m, 2H), 3.65(s, 3H), 3.55-3.61 (m, 4H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 818 (M+H)⁺ (ES⁺)

Method 2

(I) Ethyl 2-[2-(2-benzyloxyethoxy)ethoxy]acetate

To a 5 L flask under nitrogen was added 60% NaH (73.5 g, 1.8375 mol) andTHF (2.3 L). The resulting slurry was cooled to 0-5° C.2-(2-Benzyloxyethoxy)ethanol (300 g, 1.5287 mol) dissolved in THF (700mL) was then added dropwise over 1 h. Exotherm and gas evolution wasobserved throughout addition and as the reaction proceeded. The reactionwas stirred for 40 mins. Ethyl bromoacetate (207 mL, 1.8375 mol) wasthen added, dropwise over 1 h, maintaining the temperature<5° C. As thereaction proceeded the mixture turned yellow in colour. The reaction wasstirred for 2 h and allowed to warm to rt. LC showed 68% product and1.6% starting material. To the reaction was added TBME (1 L) and water(1 L). The organics were separated and the aqueous phase re-extractedwith TBME (2 L and 1 L). The combined organics were dried, filtered andconcentrated in vacuo. The residue (462 g) was purified on silica (3 kg)eluting with 10% EtOAc:heptane (20 L), 20% EtOAc:heptane (10 L), 25%EtOAc:heptane (20 L) and 30% EtOAc:heptane (10 L). Theproduct-containing fractions were concentrated in vacuo to give 322.6 g(74% yield) of the sub-title compound, for which ¹H NMR analysisindicated a purity of >95%.

¹H NMR (400 MHz, CDCl₃) δ: 7.25-7.37 (m, 5H), 4.58 (s, 2H), 4.22 (q,2H), 4.16 (s, 2H), 3.63-3.76 (m, 8H), 1.28 (t, 3H).

(II) Ethyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate

To a 5 L flask under nitrogen was charged 10% Pd/C (32 g), this wasfollowed by the addition of the product of step (I) above (320 g, 1.133mol) dissolved in EtOH (3.2 L). The reaction was purged with hydrogenfor 4 h and then stirred under a hydrogen atmosphere overnight. ¹H NMRindicated 2.5% starting material remaining, and so the reaction waspurged with hydrogen for 2 h. ¹H NMR then indicated complete reaction.The reaction mixture was filtered through Celite and washed with ethanol(1 L). The filtrate was concentrated in vacuo to give the sub-titlecompound. The residue was then concentrated in vacuo from toluene (300mL) and DCM (2×300 mL) to remove any traces of ethanol which may reactin the next stage. A total of 217.8 g of the sub-title compound (100%yield) was obtained, accounting for solvent.

Alternatively, the sub-title compound was prepared by the followingmethod:

To a 20 L vessel under nitrogen was charged 10% Pd/C (100 g), this wasfollowed by the addition of the product of step (I) above (1003 g),dissolved in DCM (10.3 L). The reaction was stirred under a hydrogenatmosphere overnight, after which NMR analysis indicated completereaction. The mixture was filtered through celite and washed with DCM(3×1 L). This product thereby obtained was used directly in the nextstep (mesylation reaction) without further purification (to give an 86%yield over steps (II) and (III)).

¹H NMR (400 MHz, CDCl₃) δ: 4.23 (q, 2H), 4.13 (s, 2H), 3.68-3.77 (m,6H), 3.59-3.63 (m, 2H), 2.51-2.57 (br m, 1H), 1.28 (t, 3H).

(II) Ethyl 2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate

To a 10 L flask under nitrogen was added the product of step (II) above(219 g, 1.139 mol), DCM (4.4 L) and triethylamine (326 mL, 2.349 mol).The solution turned yellow on addition of the triethylamine. Thesolution was cooled to 0-5° C. and methanesulfonyl chloride (108.5 mL,1.4 mol) was added dropwise. The reaction was allowed to warm to 8° C.,at which point TLC of the reaction mixture indicated complete reaction.The reaction was concentrated in vacuo. The residue was partitionedbetween ethyl acetate (4.4 L) and water (2 L). The organics wereseparated and washed with sat. aqueous NaHCO₃ (2 L) and brine (2 L). Theaqueous phase was back extracted with ethyl acetate (1 L). The combinedorganics were dried, filtered and concentrated in vacuo to give thesub-title compound as a red oil (297 g, 97%).

(IV) Ethyl 2-(2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethoxy)acetate

To a 5 L flange flask under nitrogen was added 3-methoxy-5-nitrophenol(126.8 g, 0.749 mol), potassium carbonate (288 g, 2.086 mol), DMF (2536mL) and the product of step (III) above (198.4 g active, 0.7348 mol).The reaction was heated to 60° C. overnight. LC indicated 95.8% productand 1.45% starting material (3-methoxy-5-nitrophenol). The reaction wascooled to rt and the reaction mixture transferred to a 20 L flask. Tothe mixture was added TBME (10 L) and water (6 L). The organics wereseparated and washed with sat. aqueous NaHCO₃ (6 L) and sat. brine (6 L)before drying, filtering and concentrating in vacuo to yield a total of243 g of the sub-title compound, accounting for solvent (95% yield). LCindicated a purity of 97.7% (254 nm).

(V) Ethyl-2-(2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethoxy)acetate

To a 5 L hydrogenation vessel was charged 5% Pd/C (48.6 g), the productof step (IV) above (243 g, 0.708 mol) and ethanol (2.5 L). The vesselwas purged with nitrogen three times and then stirred under a hydrogenatmosphere at 5 bar (0.5 MPa) (purged three times with hydrogen) for 6h. LC indicated complete reaction. The mixture was filtered and washedwith ethanol (1200 mL). The organics were then concentrated in vacuo.The residue was then concentrated from heptane (2×500 mL). This gave 212g (96% yield) of the sub-title compound, for which LC indicated a purityof 98.1% (254 nm). ¹H NMR indicated a purity of >95%.

(VI) Ethyl2-(2-(2-(3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)-amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

To a 5 L flange flask under nitrogen was added the product of step (V)above (190 g, 0.6065 mol), tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, WO 2014/162126; 246.9 g, 0.6658 mol), DMF (3.4 L) and potassiumcarbonate (272 g, 1.97 mol). The reaction was vacuum degassed threetimes and released to nitrogen each time. The resulting slurry washeated to 40° C. and then Brettphos G3 Pd (13.66 g, 0.015 mol) wasadded. The mixture was then heated to 70° C. and stirred for 30 mins. LCindicated <1% of the product of step (V) above remaining. This wasconfirmed by NMR. The reaction was cooled to rt and filtered, then thesolid was washed with DMF (700 mL). The filtrate was then concentratedin vacuo. The residue was dissolved in ethyl acetate (6 L) and washedwith sat. brine (2×4 L). The organics were then dried, filtered andconcentrated in vacuo. This gave 393 g (100% yield, accounting forsolvent) of the sub-title compound, for which NMR indicated a purity of˜95% and LC indicated a purity of 94.5% (254 nm).

Alternatively, the sub-title compound was prepared by the followingmethod:

To a 50 L vessel under nitrogen was charged the product of step (V)above (967 g) and THF (17425 mL). This was followed by tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, WO 2014/162126; 1254 g) and potassium carbonate (1387 g). Thevessel was vacuum degassed (×3) and released to nitrogen (×3). Thereaction was then charged with Pd-173 (39.2 g). The reaction was heatedto reflux overnight, after which LC analysis indicated trace startingmaterial. The reaction was cooled to 60° C. and further Pd-173 (6.13 g)was added. The reaction was heated to reflux for 1 h, after which LCanalysis indicated complete reaction. The reaction mixture was filteredand the residue washed with THF (9.2 L). The filtrate was concentratedin vacuo and the residue concentrated from ethyl acetate and heptane toremove the residual THF. The material was then purified viachromatography (12 kg silica), eluting with 50% ethyl acetate:heptane(60 L), 70% ethyl acetate:heptane (60 L) and 85% ethyl acetate:heptane(20 L). This gave 1896 g (95% yield, accounting for solvent (EtOAc)) ofthe sub-title compound, for which NMR indicated a purity of >95%,excluding solvent, and LC indicated a purity of 97.4%.

¹H NMR (400 MHz, CDCl₃) δ: 8.06 (d, 1H), 7.96 (d, 2H), 7.80-7.88 (br d,1H), 7.48-7.60 (m, 2H), 7.20 (d, 1H), 6.98 (br s, 1H), 6.61 (s, 1H),6.38-6.41 (m, 4H), 6.13 (m, 1H), 4.10-4.24 (m, 4H), 3.90-3.94 (m, 2H),3.77-3.83 (m, 6H), 3.68 (s, 3H), 1.57 (s, 9H), 1.24-1.30 (m, 3H).

(VII) Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy)-phenoxy)ethoxy)ethoxy)acetate

To a 5 L flange flask under nitrogen was added the product of step (VI)above (393 g, 0.6067 mol), DCM (1.742 L) and TFA (350 mL, 4.57 mol). Thereaction was heated to 30° C. overnight, after which LC analysisindicated 18% starting material remaining. TFA (100 mL) was added to thereaction, which was then heated to reflux for 2 h. LC indicated 1.2%starting material remaining. The reaction was cooled to rt andconcentrated in vacuo. The residue was azeotroped with toluene (1 L).The residue was diluted with ethyl acetate (3 L) and treated carefullywith sat aqueous NaHCO₃ (4 L), at which point off-gassing was observed.The organics were separated and washed with more sat. aqueous NaHCO₃ (2L). The combined aqueous phase was basic as required. The aqueous phasewas extracted with ethyl acetate (1 L). The combined organics weredried, filtered and concentrated in vacuo. The residue was subjected tochromatography (4.5 kg silica), eluting with DCM to 5% MeOH:DCM. Theproduct-containing fractions were combined and concentrated in vacuo. Atotal of 292 g of the sub-title compound (accounting for DCM) wasobtained (80% yield), for which ¹H NMR analysis indicated >95% purityand LC indicated a purity of 98.5% (254 nm).

(VIII) Ethyl2-(2-(2-(3-methoxy-5-((4-((4-(phenoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)phenoxy)ethoxy)ethoxy)acetate

To a 50 L vessel was charged the product of step (VII) above (1478 g ofthat product contained ˜10% THF) and THF (20.825 L). This was followedby the addition of NaHCO₃ (339.7 g). The mixture was cooled to −10° C.and charged with phenyl chloroformate (338.5 mL). The reaction wasstirred for 1 h, after which LC indicated 97.5% product and 0.9%starting material. The reaction was then warmed to rt, at which point LCindicated 98% product and 0.32% starting material. The reaction mixturewas filtered and washed with THF (2.5 L). The residue was concentratedto 2.6 kg before being dissolved in ethyl acetate:THF (2.9 L:262 mL) andthen added by vacuum transfer to a 50 L vessel containing heptane(26.715 L). This led to precipitation of the product. The mixture wasstirred for 2 h and filtered. The solids were then dried under vacuum at40° C. overnight. A total of 1843 g (102% yield, accounting for solvent)of the sub-title compound was obtained, for which NMR indicated a purityof >95%, excluding solvents, and LC indicated a purity of 95.9%.

¹H NMR (400 MHz, (CD₃)₂SO) δ: 10.00-10.40 (br, 2H), 8.28 (d, 1H), 8.01(d, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.60-7.71 (m, 2H), 7.39-7.50 (m,3H), 7.22-7.28 (m, 3H), 6.78 (dd, 1H), 6.56 (s, 1H), 6.49 (s, 1H),6.24-6.29 (m, 2H), 4.02-4.09 (4H), 3.96-3.99 (m, 2H), 3.62-3.69 (m, 5H),3.50-3.58 (m, 4H), 1.14 (t, 3H).

(IX) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamidophenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

To a 10 L flask under nitrogen was added the product of step (VII) above(262.8 g, 0.4799 mol), dissolved in iPrOAc (3.15 L). The mixture washeated to 40° C. and phenylN-(5-(tert-butyl)-2-methoxy-3-((methylsulfonyl)amino)phenyl)carbamate(see, for example, WO 2014/162126; 197.1 g, 0.5022 mol) was added. Themixture was further heated to 50° C. to give a solution which wassubsequently treated with triethylamine (13.14 mL, 0.094 mol) and thereaction heated to 68° C. overnight. The reaction was cooled to rt andconcentrated in vacuo. A portion of the residue (38 g) was purified viachromatography eluting with 25% EtOAc:DCM to EtOAc. The productcontaining fractions were concentrated in vacuo, and LC analysis (at 254nm) indicated a purity of 98.6% for the remainder. This material wascombined with the bulk and purified on silica (10 kg) eluting with 25%EtOAc:DCM (80 L), DCM (20 L), 1% MeOH:DCM (20 L), 3% MeOH:DCM (20 L) and5% MeOH:DCM (50 L). The product containing fractions were combined andconcentrated in vacuo. This gave 375 g of material with a LC purity of95.4% and NMR purity of ˜90%. This material further purified viachromatography (10 kg silica). The column was eluted with 1% MeOH:DCM(60 L), 1.5% MeOH:DCM (20 L), 2% MeOH:DCM (20 L), 2.5% MeOH:DCM (20 L),3% MeOH:DCM (40 L) then 5% MeOH:DCM (40 L). The purest fractions werecombined and concentrated in vacuo to give 324 g of the sub-titlecompound, for which LC analysis (at 254 nm) indicated a purity of 98.9%and NMR indicated a purity of ˜95%.

Alternatively, the sub-title compound was prepared by the followingmethod:

The product of step (VIII) above (1902 g) and THF (19.02 L) were chargedto a reaction vessel. The reaction was then charged withN-(3-amino-5-(tert-butyl)-2-methoxyphenyl)methanesulfonamide (see, forexample, Cirillo, P. F. et al., WO 2002/083628, 24 Oct. 2002; 815 g) andtriethylamine (380.4 mL). The reaction was heated to reflux overnight,after which LC analysis indicated complete reaction (86% product and0.4% starting material). The reaction was cooled to rt and filtered toremove triethylamine hydrochloride. The solids were washed with THF (3.8L). The filtrate was split into 3 equal portions and concentrated. Theportions were then concentrated from 40% ethyl acetate:heptane (3 L) toremove the majority of THF, which would affect column chromatography.Each of the three portions was purified via chromatography (10 kg silicaper portion, with the crude material loaded on to the column with 2 L ofDCM), eluting with 75% ethyl acetate:heptane (20 L), 80% ethylacetate:heptane (120 L) and then 85% ethyl acetate:heptane (40 L). Thisgave material with a 98.0% purity by LC and a purity by NMR analysisof >95%, excluding solvents. The sub-title compound was isolated in 83%yield (687 g).

¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.38 (s, 1H), 9.15 (s, 1H), 8.92 (s, 1H),8.88 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.09-8.13 (m, 2H), 7.86 (d,1H), 7.70 (t, 1H), 7.60 (t, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.90 (s,1H), 6.79 (s, 1H), 6.57 (dd, 1H), 6.02-6.08 (m, 2H), 4.09-4.13 (m, 4H),3.96-3.99 (m, 2H), 3.80 (s, 3H), 3.69-3.72 (m, 2H), 3.58-3.65 (m, 7H),3.10 (s, 3H), 1.27 (s, 9H), 1.18 (t, 3H).

(X)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

To a 10 L flask under nitrogen was added the product of step (IX) above(317 g, 0.374 mol), THF (2.54 L) and methanol (950 mL). This wasfollowed by the addition of 2 M NaOH (633 mL, 1.266 mol), at which pointa small exotherm was noted. The reaction was stirred for 1 h. LCanalysis indicated complete reaction. To the reaction was added aceticacid (633 mL), which again caused a small exotherm to be noted. Thereaction mixture was then concentrated in vacuo to give a viscous oil.Water (3.2 L) was added and the mixture stirred for 20 mins. Initiallyan oily solid stuck to side of flask, this was scraped from the side ofthe vessel with a spatula, the solid became a mobile, flocculent solid.The solid was filtered and washed with water (500 mL) and heptane (1.5L). The solid was then dried overnight under vacuum at 50° C., beforebeing dissolved in 10% methanol:DCM and subjected to chromatography (6kg silica) eluting with 10% methanol:DCM (60 L), 20% methanol:DCM (60 L)then methanol. The cleanest fractions were combined and concentrated invacuo to give a viscous oil. The residue was concentrated from THF (2×2L) to give a foamy solid. The solid (297 g) contained 8.55% THF and2.29% AcOH. The material was slurried in water (900 mL) overnight twiceand filtered to give 268 g of the title compound (262 g, accounting forsolvent, 85% yield) with a purity of 98.2% by LC analysis and a purityof >95% by NMR. The material contained 2.11% THF and 0.26% AcOH.

Example 4

The following compounds are prepared by methods analogous to thosedescribed above.

(a)2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)aceticacid

(b)2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyPhenyi)sulfinyl)ethoxy)ethoxy)aceticacid

(c)2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)aceticacid

(d)2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)aceticacid

(e)2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethyl)phenoxy)ethoxy)ethoxy)aceticacid

(f)6-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamide)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)pyridazine-3-carboxylicacid

(g)5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(methoxyphenoxy)ethoxy)methyl)-1,2,4-oxadiazole-3-carboxylicacid

(h)2-(2-(2-(3-((4-((4-(3-(5=(tert-Butyl)-2-(methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i)1-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)cyclopropane-1-carboxylicacid

(j)4-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-2-carboxylicacid

(k)1-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-3-methyl-1H-pyrazole-4-carboxylicacid

(l)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethylphenoxy)ethoxy)ethoxy)aceticacid

Example 52-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-(methoxy-d3)-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) 5-(tert-butyl)-2-(methoxy-d3)-1,3-dinitrobenzene

A mixture of 4-(tert-butyl)-2,6-dinitrophenol (5 g, 20.81 mmol), caesiumcarbonate (13.56 g, 41.6 mmol) and iodomethane-d3 (1.6 mL, 25.7 mmol) inDMF (50 mL) was stirred at rt for 4 days then partitioned between ether(300 mL) and water (300 mL). The organic layer was separated, washedwith water (200 mL), dried (MgSO₄), filtered and evaporated underreduced pressure to afford the sub-title compound (4.3 g) as a yellowsolid.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 2H), 1.40 (s, 9H).

(ii) 5-(tert-Butyl)-2-(methoxy-d3)-3-nitroaniline

10% Pd/C (500 mg, Type 39, 50% w/w paste with water) was added to asolution of the product from step (i) above (4.25 g, 16.52 mmol) andcyclohexene (2.5 mL, 24.68 mmol) in EtOH (70 mL). The reaction mixturewas heated at 70° C. for 1 h then a further portion of cyclohexene (5mL) was added. After heating for 1 h, a third portion of cyclohexene (5mL) was added, heated for 2 h then the reaction mixture cooled andfiltered through celite. The filtrate was evaporated under reducedpressure and the residue dissolved in EtOAc/ether (300 mL, 1/1), washedwith 0.2M aq HCl (2×150 mL), brine (200 mL), dried (MgSO₄), filtered andevaporated under reduced pressure to afford the sub-title compound (3.43g) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, 1H), 7.05 (d, 1H), 1.31 (s, 9H).

m/z 228 (M+H)⁺ (ES⁺)

(iii) N-(5-(tert-Butyl)-2-(methoxy-d3)-3-nitrophenyl)methanesulfonamide

To a stirred solution of the product from step (ii) above (3.42 g, 15.05mmol) in DCM (25 mL) at 0-5° C., was added pyridine (7 mL, 87 mmol) thenMsCl (1.9 mL, 24.38 mmol). The mixture was warmed to rt and stirred for3 days. The mixture was poured into 1 M HCl (200 mL) and extracted withDCM (200 mL). The organic phase was washed with 1 M HCl (100 mL) andbrine (100 mL), then dried (MgSO₄), filtered and concentrated in vacuo.The crude product was purified by chromatography on silica gel (120 gcolumn, 0-40% EtOAc/isohexane) to afford the sub-title compound (3.9 g)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.66 (s, 1H), 7.06 (s, 1H), 3.09(s, 3H), 1.36 (s, 9H).

(iv) N-(3-Amino-5-(tert-butyl)-2-(methoxy-d3)phenyl)methanesulfonamide

A mixture of the product from step (iii) above (3.85 g, 12.61 mmol) and10% Pd—C (500 mg) in EtOH (40 mL) was hydrogenated at 5 bar for 4 h. Themixture was filtered through celite, washing with EtOAc. The filtratewas evaporated under reduced pressure to give a solid that wastriturated with ether/isohexane. The solid was filtered and dried toafford the sub-title compound (2.92 g) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 6.58 (s, 2H), 4.91 (s, 2H),3.00 (s, 3H), 1.20 (s, 9H).

m/z 276 (M+H)⁺ (ES⁺)

(v) Phenyl(5-(tert-butyl)-2-(methoxy)-d3)-3-(methylsulfonamido)phenylcarbamate

Phenyl chloroformate (470 μL, 3.75 mmol) was added to a mixture of theproduct from step (iv) above (1 g, 3.63 mmol) and NaHCO₃ (0.610 g, 7.26mmol) in DCM (20 mL) and THF (10 mL). The mixture was stirred for 20 hthen THF (10 mL) was added followed by phenyl chloroformate (150 μL).The mixture was stirred for 5 h then partitioned between DCM (100 mL)and water (50 mL). The organic layer was separated, dried (MgSO₄),filtered and evaporated under reduced pressure. The residue wastriturated with ether/isohexane, filtered and dried to afford thesub-title compound (1.415 g, 3.54 mmol, 98% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.01 (bs, 1H), 7.46-7.42 (m, 2H), 7.35 (bs,1H), 7.32-7.27 (m, 2H), 7.25-7.21 (m, 2H), 6.78 (s, 1H), 3.11 (s, 3H),1.32 (s, 9H).

m/z 396 (M+H)⁺ (ES⁺)

(vi) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-(methoxy-d3)-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy)phenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 200 mg, 0.365 mmol) and the product from step(v) above (152 mg, 0.383 mmol) were dissolved in iPrOAc (3 mL, 25.6mmol) and NEt₃ (10.1 μL, 0.073 mmol) added. The mixture was stirred at75° C. for 16 h and concentrated in vacuo. Crude LCMS showed thesub-title compound to be the major component.

m/z 849.3 (M+H)⁺ (ES⁺)

The crude product was purified by chromatography on silica gel (12 gcolumn, 0-5% MeOH/DCM) to afford a white solid (213 mg) that was useddirectly in step (ii) below.

(vii)2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-(methoxy-d3)-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yloxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

A stirred solution of the product from step (vi) above (213 mg, 0.251mmol) in THF (10 mL) and EtOH (4 mL) was treated with NaOH (2M aq.)solution (0.452 mL, 0.903 mmol) and stirred at rt overnight. the mixturewas treated with AcOH (0.5 mL, 8.73 mmol) and concentrated in vacuo. Theresidue was triturated with water (10 mL) and filtered. The filtrate wastreated with formic acid (0.2 mL) and left to precipitate for 48 h thenfiltered. The combined solids were taken on to purification.

A total of 208 mg crude product was purified by chromatography (RP FlashC18, 26 g column, 15-50% MeCN/10 mM Ammonium Bicarbonate) to afford thetitle compound (128 mg) as a light pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (s, 1H), 8.92 (s, 1H),8.88 (s, 1H) 8.30 (d, 1H), 8.19 (d, 1H), 8.11 (dd, 2H), 7.87 (dd, 1H),7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.91 (t,1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.05-3.95(m, 4H), 3.71 (dd, 2H), 3.66 (s, 3H), 3.60 (s, 4H), 3.10 (s, 3H), 1.27(s, 9H).

m/z 821.3 (M+H)⁺ (ES⁺)

Example 62-(2-(2-(3-((4-((4-(3-(5-tert-Butyl-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-N-(methylsulfonyl)acetamide

DIPEA (71.1 μL, 0.407 mmol) was added to a solution of2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid (see Example 3 above; 111 mg, 0.136 mmol) and methanesulfonamide(19.36 mg, 0.204 mmol) in dry DMF (2 mL) at rt, followed by HATU (77 mg,0.204 mmol). The resulting yellow coloured solution was stirred at rtfor 3 h. Further portions of methanesulfonamide (19.36 mg, 0.204 mmol),DIPEA (71.1 μL, 0.407 mmol) and HATU (77 mg, 0.204 mmol) were added tothe reaction and the resulting solution stirred at rt for 1.5 h. Thereaction was then partioned between EtOAc (10 mL) and water (10 mL). Theaqueous layer was extracted with EtOAc (2×10 mL). The organic layerswere combined, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by chromatography (RP Flash C18, 12 g column,15-50% MeCN/10 mM Ammonium Bicarbonate). The product-rich fractions werecombined, the pH adjusted to 4 with formic acid and the solvent removedin vacuo The resulting solid was dried at 40° C. under vacuum overnightto afford the title compound (11 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.92 (s, 1H), 8.87 (s, 1H),8.30 (d, 1H), 8.19 (d, 2H), 8.12 (d, 1H), 8.10 (d, 1H), 7.87 (d, 1H),7.70 (ddd, 1H), 7.61 (dd, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.90-6.75 (m,2H), 6.57 (dd, 1H), 6.09 (d, 1H), 6.05 (t, 1H), 3.96 (dd, 2H), 3.81 (s,3H), 3.71-3.66 (m, 7H), 3.56 (s, 3H), 3.10 (s, 3H), 2.74 (s, 3H), 1.27(s, 9H).

m/z 895.5 (M+H)⁺ (ES⁺)

Example 72-(2-(2-(3-(4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-2-methoxy)-3-(methylcarbamoyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 125 mg, 0.228 mmol) was dissolved in iPrOAc (3mL) at 50° C., and phenyl(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)carbamate (see WO2014/162126; 85 mg, 0.240 mmol) added to the solution. The resultingmixture was stirred at 50° C. until the mixture became a solution (ca. 5min) then NEt₃ (6.36 μL, 0.046 mmol) added. The resulting solution washeated to 75° C. (block temperature) and left to stir for 16 h. Thereaction was cooled to rt and the solvent removed in vacuo. The crudeproduct was purified by chromatography on silica gel (12 g column, 0-5%MeOH/DCM to afford the sub-title compound (161 mg) as a colourlessglass.

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.88 (d. 2H), 8.44 (d, 1H).8.29 (d, 1H), 8.17 (q, 1H), 8.14-7.99 (m, 2H), 7.87 (d, 1H), 7.71 (ddd,1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.11 (d, 1H), 6.91 (t, 1H), 6.79 (t,1H), 6.57 (dd, 1H), 6.09 (d, 1H), 6.04 (t, 1H), 4.16-4.04 (m, 4H),4.03-3.94 (m, 2H), 3.80 (s, 3H), 3.76-3.68 (m, 2H), 3.65 (s, 3H),3.64-3.47 (m, 4H), 2.82 (d, 3H), 1.28 (s, 9H), 1.18 (t, 3H).

m/z 810.6 (M+H)⁺ (ES⁺)

(ii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (350 μL, 0.700 mmol) was added to a solution of thecompound from step (i) (161 mg, 0.199 mmol) in THF (1.6 mL) and MeOH(0.6 mL) and the resulting yellow solution stirred at rt for 3 h. Thereaction was acidified with AcOH (82 μL, 1.427 mmol) and concentrated invacuo. The crude product was purified by chromatography (RP Flash C18 24g column, 15-75% MeCN/10 mM Ammonium Bicarbonate). The product-richfractions were combined and the pH adjusted to pH 6 with formic acid.The volatile solvent was removed in vacuo. A precipitate formed and wascollected by filtration to afford the title compound (70 mg) as a whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.46 (s, 1H), 8.88 (d, 2H),8.44 (d, 1H), 8.29 (d, 1H), 8.17 (q, 1H), 8.11 (d, 1H), 8.08 (d, 1H),7.87 (dd, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.11 (d,1H), 6.90 (t, 1H), 6.79 (t, 1H), 6.57 (dd, 1H), 6.09 (d, 1H), 6.04 (t,1H), 4.03 (s, 2H), 3.98 (dd, 2H), 3.80 (s, 3H), 3.75-3.68 (m, 2H), 3.65(s, 3H), 3.63-3.52 (m, 4H), 2.82 (d, 3H), 1.28 (s, 9H).

m/z 782.0 (M+H)⁺ (ES⁺)

Example 82-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy)-3-(methylsulfinyl)phenylureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i)2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy)-3-(methylsulfinyl)phenylureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 125 mg, 0.228 mmol) was dissolved in iPrOAc (2mL) at 50 C, and phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)carbamate (see WO2015/092423; 87 mg, 0.240 mmol) added to the solution. The resultingmixture was stirred at 50° C. until the mixture became a solution (ca. 2min) then NEt₃ (6.36 μL, 0.046 mmol) added. The resulting solution washeated to 75° C. (block temperature) and left to stir for 16 h. Thereaction was cooled to rt and the solvent removed in vacuo. The crudeproduct was purified by chromatography on silica gel (12 g column, 0-5%MeOH/DCM) to afford the sub-title compound (172 mg) as a colourlessglass.

¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.96 (s, 1H), 8.87 (s, 1H),8.50 (d, 1H), 8.28 (d, 1H), 8.18-8.05 (m, 2H), 7.89-7.83 (m, 1H), 7.71(ddd, 1H), 7.61 (ddd, 1H), 7.46-7.31 (m, 2H), 6.91 (t, 1H), 6.79 (t,1H), 6.58 (dd, 1H), 6.09 (d, 1H), 6.04 (t, 1H), 4.18-4.06 (m, 4H),4.03-3.93 (m, 2H), 3.87 (s, 3H), 3.76-3.67 (m, 2H), 3.66 (s, 3H),3.63-3.55 (m, 4H), 2.79 (s, 3H), 1.32 (s, 9H), 1.18 (t, 3H).

m/z 815.5 (M+H)⁺ (ES⁺)

(ii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Buty)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (350 μL, 0.700 mmol) was added to a solution of thecompound from step (i) above (172 mg, 0.211 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting yellow solution stirred at rt for 3 h.The reaction was acidified with AcOH (82 μL, 1.427 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-50% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were combined and the pH adjusted to pH 5 withformic acid. The solvent was removed to afford the title compound (130mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.03 (s, 1H), 8.88 (s, 1H),8.50 (d, 1H), 8.30 (d, 1H), 8.14-8.03 (m, 2H), 7.87 (dd, 1H), 7.70 (ddd,1H), 7.65-7.54 (m, 1H), 7.39 (d, 1H), 7.36 (d, 1H), 6.84 (s, 1H), 6.77(t, 1H), 6.58 (dd, 1H), 6.10 (d, 1H), 6.03 (t, 1H), 3.99 (s, 2H), 3.94(t, 2H), 3.86 (s, 3H), 3.70 (dd, 2H), 3.65 (s, 3H), 3.62-3.55 (m, 4H),2.79 (s, 3H), 1.32 (s, 9H).

m/z 787.0 (M+H)⁺ (ES⁺)

Example 92-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxphenoxy)ethoxy)ethoxy)aceticacid

(i) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 125 mg, 0.228 mmol) was dissolved in iPrOAc (2mL) at 50° C., and phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)-carbamate (see WO2015/092423; 90 mg, 0.240 mmol) added to the solution. The resultingmixture was stirred at 50° C. for ca 5 min, then THF (1 mL) was added.The reactants went into solution then NEt₃ (6.36 μL, 0.046 mmol) added.The resulting solution was heated to 75° C. (block temperature) and leftto stir for 16 h. The reaction was cooled to rt and the solvent removedin vacuo. The crude product was purified by chromatography on silica gel(12 g column, 0-5% MeOH/DCM) to afford the sub-title compound (151 mg)as a colourless glass.

¹H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.08 (s, 1H), 8.87 (s, 1H),8.68 (d, 1H), 8.29 (d, 1H), 8.12 (s, 1H), 8.10 (d, 1H), 7.88 (dt, 1H),7.72 (ddd, 1H), 7.62 (ddd, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 6.91 (t,1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.09 (d, 1H), 6.04 (t, 1H), 4.19-4.06(m, 4H), 4.04-3.97 (m, 2H), 3.95 (s, 3H), 3.78-3.69 (m, 2H), 3.66 (s,3H), 3.64-3.55 (m, 4H), 3.35 (s, 3H), 1.32 (s, 9H), 1.18 (t, 3H).

LCMS m/z 831.5 (M+H)+ (ES+)

(ii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (350 μL, 0.700 mmol) was added to a solution of thecompound from step (i) (151 mg, 0.182 mmol) in THF (1.6 mL) and MeOH(0.6 mL) and the resulting yellow solution stirred at rt for 3 h. Thereaction was acidified with AcOH (82 μL, 1.427 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-50% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were combined and adjusted to pH 5 with formicacid. The solvent was removed to afford the title compound (114 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.49 (s, 1H), 9.10 (s, 1H),8.87 (s, 1H), 8.68 (d, 1H), 8.29 (d, 1H), 8.14-8.05 (m, 2H), 7.95-7.80(m, 1H), 7.72 (ddd, 1H), 7.62 (ddd, J=8.1, 1H), 7.45 (d, 1H), 7.40 (d,1H), 6.89 (t, 1H), 6.78 (t, 1H), 6.58 (dd, 1H), 6.10 (d, 1H), 6.04 (t,1H), 4.02 (s, 2H), 4.00-3.92 (m, 5H), 3.76-3.68 (m, 2H), 3.65 (s, 3H),3.63-3.56 (m, 4H), 3.34 (s, 3H), 1.32 (s, 9H).

m/z 803.0 (M+H)⁺ (ES⁺)

Example 102-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-3-(dimethylphosphoryl)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(dimethylphosphoryl)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 125 mg, 0.228 mmol) was dissolved in iPrOAc (2mL) at 50° C., and phenyl(5-(tert-butyl)-3-(dimethylphosphoryl)-2-methoxyphenyl)-carbamate (seeWO 2015/092423; 90 mg, 0.240 mmol) added to the solution. The resultingmixture was stirred at 50° C. for ca. 5 min and THF (1 mL) added. NEt₃(6.36 μL, 0.046 mmol) was added and the resulting mixture was heated to75° C. (block temperature) and the resulting solution left to stir for16 h at 75° C. The reaction was cooled to rt and the solvent removed invacuo. The crude product was purified by chromatography on silica gel(12 g column, 0-10% MeOH/DCM) to afford the sub-title compound (169 mg)as a pale pink glass.

¹H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.87 (s, 1H), 8.45 (s, 1H),8.28 (d, 1H), 8.11 (d. 1H), 8.08-8.03 (m, 2H), 7.87 (d, 1H), 7.71 (t,1H), 7.65-7.57 (m, 1H), 7.43-7.34 (m, 2H), 6.90 (t, 1H), 6.79 (t, 1H),6.57 (dd, 1H), 6.09 (d, 1H), 6.04 (t, 1H), 4.19-4.05 (m, 4H), 4.03-3.94(m, 2H), 3.71 (s, 2H), 3.65 (s, 3H), 3.64-3.53 (m, 4H), 2.58 (s, 3H),1.78 (s, 3H), 1.75 (s, 3H), 1.30 (s, 9H), 1.18 (t, 3H).

m/z 829.5 (M+H)⁺ (ES+)

(ii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-3-(dimethylphosphoryl)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (350 μL, 0.700 mmol) was added to a solution of thecompound from step (i) above (169 mg, 0.204 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting solution stirred at rt for 3 h. Thereaction was acidified with AcOH (82 μL, 1.427 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-50% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were combined and the pH adjusted to pH 5 withformic acid. The solvent was removed to afford the title compound (131mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.00 (s, 1H), 8.87 (s, 1H),8.42 (d, 1H), 8.31 (d, 1H), 8.16-8.06 (m, 2H), 7.87 (dd, 1H), 7.70 (ddd,1H), 7.61 (ddd, 1H), 7.41-7.31 (m, 2H), 6.85 (t, 1H), 6.77 (t, 1H), 6.58(dd, 1H), 6.09 (d, 1H), 6.03 (t, 1H), 3.99-3.92 (m, 4H), 3.90 (s, 3H),3.74-3.67 (m, 2H), 3.65 (s, 3H), 3.62-3.53 (m, 4H), 1.76 (s, 3H), 1.73(s, 3H), 1.31 (s, 9H).

m/z 801.0 (M+H)⁺ (ES⁺)

Example 112-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 125 mg, 0.228 mmol) was dissolved in iPrOAc (2mL) at 50° C., and phenyl(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)-phenyl)carbamate(see WO 2016/051187; 97 mg, 0.240 mmol) added to the solution. Theresulting mixture was stirred at 50° C. for ca 5 min, upon which thereactants dissolved. NEt₃ (6.36 μL, 0.046 mmol) added and the resultingsolution was heated to 75° C. (block temperature) and the solution wasleft to stir for 4 h at 75° C. The solvent was removed and the crudeproduct purified by chromatography on silica gel (12 g column, 0-5%MeOH/DCM) to afford the sub-title compound (83 mg) as a pale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.93 (s, 1H), 8.87 (s, 1H),8.33 (d, 1H), 8.29 (d, 1H), 8.11 (d, 1H), 8.10 (d, 1H), 7.87 (dd, 1H),7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.91 (t,1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.19-4.03(m, 4H), 3.98 (dd, 2H), 3.89 (s, 3H), 3.71 (dd, 2H), 3.65 (s, 3H),3.64-3.56 (m, 4H), 3.25 (s, 3H), 3.15 (s, 3H), 1.29 (s, 9H), 1.18 (t,3H).

m/z 860.5 (M+H)⁺ (ES+)

(ii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (175 μL, 0.350 mmol) was added to a solution of thecompound from step (i) above (83 mg, 0,097 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting yellow solution stirred at rt for 3 h.The reaction was acidified with AcOH (82 μL, 1.427 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-50% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were combined and the pH adjusted to pH 5 withformic acid. The solvent was removed to yield the title compound (57 mg)as a pale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H),8.36 (d, 1H), 8.31 (d, 1H), 8.15-8.04 (m, 2H), 7.90-7.82 (m, 1H), 7.67(ddd, 1H), 7.59 (ddd, 1H), 7.37 (d, 1H), 7.02 (d, 1H), 6.74 (d, 2H),6.60 (dd, 1H), 6.12 (d, 1H), 6.02 (t, 1H), 3.93-3.82 (m, 5H), 3.78 (s,2H), 3.72-3.66 (m, 2H), 3.65 (s, 3H), 3.59-3.51 (m, 4H), 3.25 (s, 3H),3.14 (s, 3H), 1.29 (s, 9H).

m/z 832.0 (M+H)⁺ (ES⁺)

Example 125-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)furan-3-carboxylicacid

(i) Methyl 5-(2-hydroxyethoxy)methyl)furan-3-carboxylate

To a stirred solution of dry ethane-1,2-diol (0.259 mL, 4.58 mmol) inDMSO (3 mL) at 0° C. was added tBuOK (141 mg, 1.260 mmol) slowly,portion-wise over 10 min. The resulting solution was further stirred for30 min at same temperature before adding TBAI (42.3 mg, 0.115 mmol). Ahomogeneous solution of methyl 5-(chloromethyl)furan-3-carboxylate (200mg, 1.146 mmol) in DMSO (1 mL) was added dropwise to the above reactionmixture and stirred at rt overnight. 3 mL MeOH was added and thereaction stirred once again overnight. Water (15 mL) was added, theaqueous layer extracted with ethyl acetate (2×15 mL) and dried overanhydrous sodium sulfate. Ethyl acetate was evaporated under reducedpressure. The crude product was purified by chromatography on silica gel(12 g column, 0-5% MeOH/DCM) to afford the sub-title compound (110 mg)as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, 1H), 6.75 (d, 1H), 4.63 (t, 1H),4.45 (s, 2H), 3.77 (s, 3H), 3.54-3.46 (m, 2H), 3.46-3.40 (m, 2H).

m/z 218.0 (M+NH₄)⁺ (ES⁺)

(ii) Methyl5-((2-(3-methoxysulfonyl)oxy)ethoxy)methyl)furan-2-carboxylate

The product from step (i) above (105 mg, 0.525 mmol) was dissolved in 1mL DCM and NEt₃ (88 μL, 0.629 mmol) and MsCl (45.0 μL, 0.577 mmol) wereadded. The reaction was stirred at rt for 2 h after which time LCMSindicated the reaction had gone to completion. The reaction was dilutedwith DCM (10 mL), washed with water (10 mL), passed through a phaseseparator and concentrated in vacuo to yield the sub-title compound (130mg) as a yellow oil that gradually hardened to a yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 8.39 (d, 1H), 6.79 (d, 1H), 4.56-4.46 (m,2H), 4.35-4.28 (m, 2H), 3.77 (s, 3H), 3.71-3.63 (m, 2H), 3.17 (s, 3H).

(iii) Methyl5-((2-(3-methoxy-5-nitrophenoxy)ethoxy)methyl)furan-3-carboxylate

3-Methoxy-5-nitrophenol (75 mg, 0.445 mmol), the product from step (ii)(130 mg, 0.467 mmol) and potassium carbonate (184 mg, 1.335 mmol) weresuspended in DMF (0.5 mL) and heated to 85° C. (block temperature)overnight. The reaction was cooled, diluted with water (15 mL) andextracted with TBME (3×15 mL). The combined organic layers were washedwith water (20 mL), brine (20 mL), dried (MgSO4), filtered andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (24 g column, 0-50% EtOAc/isohexane) to afford thesub-title compound (124 mg) as a yellow oil that gradually became a paleyellow waxy solid.

¹H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1H), 7.34 (d, 2H), 6.98 (t, 1H),6.78 (d, 1H), 4.53 (d, 2H), 4.28-4.20 (m, 2H), 3.86 (s, 3H), 3.82-3.71(m, 5H).

m/z 369.0 (M+NH₄)⁺ (ES⁺)

(iv) Methyl5-((2-(3-amino-5-methoxyphenoxy)ethoxy)methyl)furan-3-carboxylate

A solution of the product from step (iii) above (120 mg, 0.342 mmol) inEtOH (20 mL) was hydrogenated in the H-Cube (10% Pd/C, 30×4 mm, Fullhydrogen, rt, 1 mL/min). A blockage resulted in the solution beingexposed to overpressure for ca. 45 mins. The reaction mixture wasconcentrated in vacuo to yield an oil that was used directly in step(v). LCMS revealed a 2:3 mixture of the sub-title compound (m/z 322.0(M+H)⁺ (ES⁺)) and methyl5-((2-(3-amino-5-methoxyphenoxy)ethoxyethoxy)methyl)tetrahydrofuran-3-carboxylate(m/z 326.0 (M+H)⁺ (ES⁺) (107 mg).

(v) Methyl5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)tetrahydrofuran-3-carboxylate(Product A) and Methyl5-((2-(3-((4-((4-(3-(5-(tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino-5-methoxyphenoxy)ethoxy)methylfuran-3-carboxylate(Product B)

A suspension of the product mixture from step (iv) above (95 mg, 0.296mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide(see WO 2014/162126; 168 mg, 0.296 mmol), freshly ground potassiumcarbonate (123 mg, 0.887 mmol), and BrettPhosG3 precatalyst (13.40 mg,0.015 mmol) in DMF (3 mL) was evacuated and backfilled with nitrogenthree times. The reaction was then heated under nitrogen at 85° C.(block temperature) for 16 h. The mixture was cooled, diluted with EtOAc(15 mL), washed with brine and concentrated onto silica gel. Attemptedchromatography on silica gel (12 g column, 0-5% (0.7 MAmmonia/MeOH)/DCM) afforded little separation and an impure mixture ofproducts were obtained after trituration with water (3 mL). The productwas further purified by chromatography on RP Flash C18 (27 g column,15-75% MeCN/10 mM Ammonium Bicarbonate) to yield Product A (30 mg) as anoff-white solid that was used in Example 13 without furtherpurification.

m/z 858.1 (approximately 75% purity at 254 nm)

Further elution of the RP column yielded Product B (20 mg) as anoff-white solid that was taken to the next step without furtherpurification.

m/z 854.1 (approximately 55% purity at 254 nm)

(vi)5-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-ylamino)-5-methoxyphenoxy)ethoxy)methyl)furan-3-carboxylicacid

Product B of step (v) above (20 mg, 0.023 mmol) was dissolved in THF (2mL) and MeOH (0.5 mL). NaOH (2M aq.) (129 μL, 0.258 mmol) was added andthe mixture stirred at rt for 1.5 h. The mixture was acidified with AcOH(0.25 mL) and concentrated in vacuo. The crude product was purified bypreparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, WatersX-Select Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water) toafford the title compound (2.4 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.99 (s, 1H), 8.89 (s, 1H),8.30 (d, 1H), 8.17 (d, 1H), 8.13-8.05 (m, 3H), 7.85 (dd, 1H), 7.69 (ddd,1H), 7.62-7.56 (m, 1H), 7.38 (d, 1H), 7.01 (d, 1H), 6.86 (t, 1H), 6.78(t, 1H), 6.63 (s, 1H), 6.58 (dd, 1H), 6.05 (d, 1H), 6.01 (t, 1H), 4.46(s, 2H), 4.01-391 (m, 2H), 3.79 (s, 3H), 3.72-3.66 (m, 2H), 3.64 (s,3H), 3.09 (s, 3H), 1.26 (s, 9H).

m/z 840.2 (M+H)⁺ (ES⁺)

Example 135-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-methylsulfonamido)phenylureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)tetrahydrofuran-3-carboxylicacid

Product A of Example 12(v) above (30 mg, 0.035 mmol) was dissolved in0.4 mL THF and 0.1 mL MeOH. NaOH (2M aq.) (192 μL, 0.385 mmol) was addedand the mixture stirred at rt for 1.5 h. The reaction was acidified withAcOH (0.25 mL) and concentrated in vacuo. The crude product was purifiedby preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water)to afford the title compound (7 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.55 (d, 1H), 8.99 (d, 1H), 8.84 (d, 1H),8.37 (s, 1H), 8.25 (dd, 1H), 8.09 (t, 1H), 8.06-8.00 (m, 2H), 7.78 (dd,1H), 7.64-7.58 (m, 1H), 7.53 (ddd, 1H), 7.31 (dd, 1H), 6.95 (d, 1H),6.78 (dt, 1H), 6.72 (q, 1H), 6.51 (ddd, 1H), 5.97 (dt, 2H), 3.90-3.83(m, 3H), 3.77-3.69 (m, 4H), 3.66-3.60 (m, 3H), 3.57 (s, 3H), 3.40-3.34(m, 2H), 3.01 (s, 3H), 2.90-2.82 (m, 1H), 2.07-1.99 (m, 1H), 1.66 (ddd,1H), 1.19 (s, 9H).

m/z 844.1 (M+H)⁺

Example 142-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid

(i) Ethyl 2-(2-(2-(benzvloxy)ethoxy)ethoxy) propanoate

2-(2-(Benzyloxy)ethoxy)ethanol (5 g, 25.5 mmol) was dissolved in DCM (50mL), passed through a phase separator and concentrated in vacuo. It wasthen redissolved in dry THF (50 mL, 25.5 mmol) under nitrogen and cooledin an ice bath. NaH (60% in mineral oil, 1.070 g, 26.8 mmol) was addedportionwise over 10 min and the resulting suspension stirred for 30 min.Ethyl 2-bromopropanoate (3.73 mL, 28.0 mmol) was added dropwise over 15min. The reaction was stirred overnight, quenched with sat. NH₄Cl (5 mL)and the resulting mixture concentrated directly onto silica gel. Thecrude product was purified by chromatography on silica gel (80 g column,0-50% EtOAc/isohexane) to afford the sub-title compound (1.51 g) as acolourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.51-7.09 (m, 5H), 4.50 (s, 2H), 4.11 (qd,2H), 4.05 (q, 1H), 3.70-3.41 (m, 8H), 1.27 (d, 3H), 1.20 (t, 3H).

(ii) Ethyl 2-(2-(2-hydroxyethoxy)ethoxy)propanoate

The product from step (i) above (1.5 g, 5.06 mmol) was dissolved in EtOH(60 mL, 5.06 mmol) and hydrogenated over Pd—C (0.539 g, 0.506 mmol) at 1bar H₂ for 16 h at rt. The reaction was filtered through celite, thesolids washed with EtOH (20 mL) and the mixture concentrated in vacuo toyield the sub-title compound (931 mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.56 (t, 1H), 4.12 (qd, 2H), 4.04 (q, 1H),3.67-3.56 (m, 1H), 3.56-3.45 (m, 5H), 3.42 (dd, 2H), 1.27 (d, 3H), 1.21(t, 3H).

(iii) Ethyl 2-(2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethoxy)propanoate

The product from step (ii) above (932 mg, 4.52 mmol) was dissolved inDCM (5 mL) and cooled in an ice bath. NEt₃ (756 μL, 5.42 mmol) and MsCl(387 μL, 4.97 mmol) were added sequentially dropwise and the reactionstirred for 1 h in the ice bath. DCM (50 mL) was added and the organiclayer washed with brine (2×50 mL), passed through a phase separator andconcentrated in vacuo to yield 1.13 g of a yellow oil. 282 mg of thisyellow oil, 3-methoxy-5-nitrophenol (160 mg, 0.946 mmol), and potassiumcarbonate (392 mg, 2.84 mmol) were suspended in DMF (3 mL) and heated to80° C. overnight. The reaction was cooled and partitioned between TBME(20 mL) and brine (20 mL). The aqueous layer was extracted with TBME (20mL) and the combined organic layers washed with brine (40 mL), dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by chromatography on silica gel (12 g column, 0-50%EtOAc/isohexane) to afford the sub-title compound (200 mg) as a yellowoil.

¹H NMR (400 MHz, DMSO-d6) δ 7.34 (dt, 2H), 7.00 (t, 1H), 4.29-4.18 (m,2H), 4.12 (ddq, 2H), 4.05 (q, 1H), 3.86 (s, 3H), 3.81-3.74 (m, 2H),3.66-3.57 (m, 3H), 3.56-3.46 (m, 1H), 1.26 (d, 3H), 1.19 (t, 3H).

(iv) Ethyl 2-(2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethoxy)propanoate

To a solution of the product from step (iii) above (200 mg, 0.560 mmol)in EtOH (30 mL) and EtOAc (7 mL) was added Pd/C (5 wt %, type 87 L)(61.3 mg, 0.029 mmol). The resulting suspension was stirred under 3 barH₂ for 1 h. The reaction mixture was filtered through celite andconcentrated in vacuo to yield the sub-title compound (130 mg) as a redoil.

¹H NMR (400 MHz, DMSO-d6) δ 5.75 (d, 2H), 5.69 (t, 1H), 5.05 (s, 2H),4.12 (qd, 2H), 4.06 (q, 1H), 4.00-3.91 (m, 2H), 3.73-3.66 (m, 2H),3.66-3.55 (m, 6H), 3.55-3.49 (m, 1H), 1.28 (d, 3H), 1.20 (t, 3H).

(v) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxphenoxy)ethoxy)ethoxy)propanoate

A solution of the product from step (iv) above (130 mg, 0.397 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 226 mg, 0.397 mmol), potassium carbonate (165 mg,1.191 mmol), and BrettPhosG3 precatalyst (18.00 mg, 0.020 mmol) in DMF(3 mL) was degassed with nitrogen for 10 mins. The reaction was heatedunder nitrogen at 85° C. (block temperature) for 2 h. The reaction wascooled and partitioned between EtOAc (10 mL) and water (10 mL). Theaqueous phase was extracted with EtOAc (5 mL). The combined organicphases were washed with brine (5 mL) dried (MgSO₄), filtered andconcentrated in vacuo affording a dark brown solid. The crude productwas purified by chromatography on silica gel (12 g column, 1-6% MeOH inDCM) to afford the sub-title compound (125 mg) as a pale beige foam.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H),8.87 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.15-8.07 (m, 2H), 7.87 (dt,1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.03 (d, 1H), 6.91(t, 1H), 6.78 (t, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.11(qd, 2H), 4.07-4.02 (m, 1H), 3.98 (dd, 2H), 3.81 (s, 3H), 3.75-3.69 (m,2H), 3.65 (s, 3H), 3.62-3.55 (m, 3H), 3.55-3.47 (m, 1H), 3.10 (s, 3H),1.31-1.23 (m, 12H), 1.19 (t, 3H).

m/z 860.1 (M+H)⁺ (ES⁺)

(vi)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid

The product from step (vi) above (120 mg, 0.140 mmol) was dissolved inTHF (2 mL) and MeOH (0.5 mL). NaOH (2M aq.) (767 μL, 1.535 mmol) wasadded and the mixture stirred at rt for 16 h. The reaction was acidifiedwith AcOH (0.25 mL) and concentrated in vacuo. The crude product waspurified by chromatography on RP Flash C18 (24 g column, 15-75% MeCN/10mM Ammonium Bicarbonate). The product containing fractions werecombined, acidified with formic acid to ca. pH 4, concentrated in vacuoand the resulting precipitate filtered off washing with water (5 mL) toafford the title compound (64 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.36-9.30 (m, 1H), 9.04 (s,1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.22 (d, 1H), 8.11 (d, 1H), 8.04 (s,1H), 8.02 (d, 1H), 7.79 (dd, 1H), 7.63 (ddd, 1H), 7.53 (ddd, 1H), 7.31(d, 1H), 6.95 (d, 1H), 6.82 (t, 1H), 6.71 (t, 1H), 6.50 (dd, 1H), 6.01(d, 1H), 5.96 (t, 1H), 3.93-3.82 (m, 3H), 3.73 (s, 3H), 3.67-3.61 (m,2H), 3.59-3.53 (m, 4H), 3.50 (dd, 2H), 3.44-3.37 (m, 1H), 3.02 (s, 3H),1.19 (s, 9H), 1.18 (d, 3H).

m/z 832.1 (M+H)⁺ (ES⁺)

Example 152-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-3-(ethylsulfonyl)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)ethoxy)ethoxy)aceticacid

(i) (5-(tert-Butyl)-2-methoxy-3-nitrophenyl)(ethyl)sulfane

Tert-butyl nitrite (3.18 mL, 26.8 mmol) was added dropwise at rt to astirred, dark brown solution of 1,2-diethyldisulfane (3.29 mL, 26.8mmol) and 5-(tert-butyl)-2-methoxy-3-nitroaniline (2 g, 8.92 mmol) inMeCN (50 mL). The reaction was then heated to reflux (block temp 80° C.)and the dark brown solution was stirred at reflux for 2 h. The reactionwas then cooled to rt and the solvent evaporated. The dark red residuewas azeotroped with toluene (3×25 mL). The crude product was purified bychromatography on silica gel (80 g column, 0-20% MTBE:isohexane) toafford the sub-title compound (1.007 g) as an orange oil. ¹H NMR (400MHz, DMSO-d6) δ 7.64 (d, 1H), 7.53 (d, 1H), 3.84 (s, 3H), 3.09 (q, 2H),1.31 (s, 9H), 1.28 (t, 3H).

(ii) 5-(tert-Butyl)-1-(ethylsulfonyl)-2-methoxy-3-nitrobenzene

m-CPBA (1.747 g, 7.80 mmol) was added to a solution of the compound fromstep (i) above (1 g, 3.71 mmol) in DCM (40 mL) under nitrogen at 0° C.and the resulting orange slurry stirred at 0° C. for 30 min then warmedto rt and stirred at rt for 2.5 h. The reaction was quenched with asolution of sodium thiosulfate (2.348 g, 14.85 mmol) dissolved in water(10 mL) and stirred at rt for 30 min. The layers were diluted with DCM(50 mL) and separated. The organic layer was washed with sat. aq. NaHCO₃(3×20 mL) and dried (MgSO₄). The solvent was removed to afford a darkred oil. The crude product was purified by chromatography on silica gel(40 g column, 20-100% DCM:heptane) to afford the sub-title compound (935mg) as a thick orange oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.32 (d, 1H), 8.06 (d, 1H), 3.94 (s, 3H),3.49 (q, 2H), 1.34 (s, 9H), 1.15 (t, 3H).

m/z 302.2 (M+H)⁺ (ES⁺)

(iii) 5-(tert-butyl)-3-(ethylsulfonyl)-2-methoxyaniline

NH₄Cl (66.4 mg, 1.241 mmol) was added to a slurry of the compound fromstep (ii) above (935 mg, 3.10 mmol) and iron (1733 mg, 31.0 mmol) inEtOH (20 mL), water (5 mL) and THF (2 mL). The resulting black slurrywas heated to reflux for 1 h. The solution was cooled to rt and filteredthrough celite, washing with EtOAc (2×20 mL). The solvent was removed invacuo. The crude product was purified by chromatography on silica gel(40 g column, 0-40% EtOAc:isohexane) to afford the sub-title compound(820 mg) as a thick yellow oil.

m/z 272.3 (M+H)+ (ES+)

(iv) Phenyl (5-(tert-butyl)-3-(ethylsulfonyl)-2-methoxyphenyl) carbamate

Phenyl chloroformate (417 μL, 3.32 mmol) was added to a slurry of thecompound from step (iii) (820 mg, 3.02 mmol) and NaHCO₃ (762 mg, 9.06mmol) in DCM (8 mL) and THF (2 mL). The resulting slurry was stirred atrt for 18 h. The reaction was diluted with DCM (10 mL) and washed withwater (10 mL) and brine (10 mL). The organic layer was concentrated invacuo to afford a light orange solid. This was triturated withcyclohexane (10 mL) and the resulting solid collected by filtration,washing with cyclohexane (2×2 mL) to afford the sub-title compound (940mg) as a beige solid.

m/z 392.3 (M+H)+ (ES+)

(v) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-3-(ethylsulfonyl)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 100 mg, 0.183 mmol) was dissolved in iPrOAc (2mL) at 50° C. and the compound from step (iv) above (75 mg, 0.192 mmol)added to the solution. The resulting mixture was stirred at 50° C. foruntil the carbamate dissolved (ca 5 min) then NEt₃ (5.09 μL, 0.037 mmol)was added and the resulting solution stirred at 75° C. for 4 h. Thesolvent was removed. The crude product was purified by chromatography onsilica gel (12 g column, 0-5% MeOH/DCM). The product was repurified bychromatography (RP Flash C18 12 g column, 15-75% MeCN/10 mM AmmoniumBicarbonate) to afford the sub-title compound (86 mg) as a light pinksolid.

¹H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.07 (s, 1H), 8.88 (s, 1H),8.70 (d, 1H), 8.29 (d, 1H), 8.14-8.04 (m, 2H), 7.88 (d, 1H), 7.71 (t,1H), 7.62 (t, 1H), 7.42 (d, 1H), 7.40 (d, 1H), 6.90 (t, 1H), 6.78 (t,1H), 6.58 (dd, 1H), 6.09 (d, 1H), 6.04 (t, 1H), 4.19-4.06 (m, 4H), 3.98(t, 2H), 3.94 (s, 3H), 3.75-3.68 (m, 2H), 3.65 (s, 3H), 3.64-3.55 (m,4H), 3.44 (q, 2H), 1.31 (s, 9H), 1.22-1.12 (m, 6H).

m/z 845.5 (M+H)+ (ES+)

(vi)2-(2-(2-(3-((4-(4-(3-(5-(tert-Butyl)-3-(ethylsulfonyl)-2-methoxyphenoxy)ureidonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (175 μL, 0.350 mmol) was added to a solution of thecompound from step (v) above (86 mg, 0.102 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting solution stirred at rt overnight. Thereaction was quenched with AcOH (24.14 μL, 0.422 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-75% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were neutralised with formic acid andconcentrated to afford the title compound (67 mg) as a light beigesolid.

¹H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.21 (s, 1H), 8.88 (s, 1H),8.69 (d. 1H), 8.32 (d, 1H), 8.14-8.07 (m, 2H), 7.87 (d, 1H), 7.76-7.66(m, 1H), 7.66-7.56 (m, 1H), 7.42 (d, 1H), 7.39 (d, 1H), 6.79 (s, 1H),6.75 (t, 1H), 6.59 (dd 1H), 6.11 (d, 1H), 6.03 (t, 1H), 3.99-3.86 (m,7H), 3.69 (dd, 2H), 3.65 (s, 3H), 3.58 (q, 4H), 3.44 (q, 2H), 1.31 (s,9H), 1.15 (q, 3H).

m/z 817.5 (M+H)⁺ (ES⁺)

Example 162-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-3-(ethylsulfonamido-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) N-(5-(tert-butyl)-2-methoxy-3-nitrophenvl)ethanesulfonamide

Ethanesulfonyl chloride (475 μL, 5.02 mmol) was added at 0° C. to asolution of 5-(tert-butyl)-2-methoxy-3-nitroaniline (750 mg, 3.34 mmol)and pyridine (1082 μL, 13.38 mmol) in DCM (10 mL). The resultingsolution was stirred at 000° C. for 5 min, then at rt for 16 h. Thereaction was washed with 2 M HCl (10 mL) and brine (10 mL) andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (12 g column, 0-20% EtOAc/isohexane) to afford thesub-title compound, 915 mg of a yellow oil that solidified on standing.The solid was triturated with ether:isohexane (1:1 ratio, 10 mL) toafford the sub-title compound (686 mg) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.68 (s, 2H), 3.82 (s, 3H),3.22 (q, 2H), 1.40-1.18 (m, 12H).

m/z 315 (M−H)−(ES−)

(ii) N-(3-amino-5-(tert-butyl-2-methoxyphenyl) ethanesulfonamide

10% Pd/C, 50% Paste in water, Type 39 (46.2 mg, 0.434 mmol) was added toa solution of the compound from step (i) above (686 mg, 2.168 mmol) inEtOH (5 mL) and EtOAc (2 mL) and the resulting slurry stirred under H₂at 5 bar pressure overnight. The reaction was filtered through celite,washing with EtOAc (50 mL). The solvent was removed in vacuo to affordthe sub-title compound (600 mg) as a light pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 6.61-6.52 (m, 2H), 4.88 (s,2H), 3.63 (s, 3H), 3.09 (q, 2H), 1.25 (t, 3H), 1.20 (s, 9H).

m/z 287.3 (M+H)+ (ES+)

(iii) Phenyl(5-(tert-butyl)-3-(ethylsulfonamido)-2-methoxyphenyl)carbamate

Phenyl chloroformate (289 μL, 2.305 mmol) was added to a slurry of thecompound from step (ii) above (600 mg, 2.095 mmol) and NaHCO₃ (528 mg,6.29 mmol) in DCM (8 mL) and THF (2 mL). The resulting slurry wasstirred at rt for 2 h. The reaction was diluted with DCM (10 mL) andwashed with water (10 mL) and brine (10 mL). The organic layer wasconcentrated in vacuo to afford an orange oil that solidified uponstanding. This was triturated with cyclohexane (10 mL) and the resultingsolid collected by filtration, washing with cyclohexane (2×2 mL) toafford the sub-title compound (788 mg, 1.842 mmol, 88% yield) as a lightbeige solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.12 (s, 1H), 7.54 (s, 1H),7.47-7.36 (m, 2H), 7.30-7.19 (m, 3H), 7.17 (d, 1H), 3.77 (s, 3H), 3.15(q, 2H), 1.28 (t, 3H), 1.24 (s, 9H).

m/z 429.4 (M+Na)+(ES+)

(iv) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(ethylsufonamido)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 100 mg, 0.183 mmol) was dissolved in iPrOAc (2mL) at 50° C. and the compound from step (iii) (97 mg, 0.240 mmol) addedto the solution. The resulting mixture was stirred at 50° C. until thecarbamate dissolved (ca 5 min). NEt₃ (5.09 μL, 0.037 mmol) was added andthe resulting solution stirred at 75° C. for 4 h. The solvent wasremoved in vacuo. Chromatography on silica gel (12 g column, 0-5%MeOH/DCM) did not afford sufficient purity. The crude product wasrepurified by chromatography (RP Flash C18 12 g column, 15-75% MeCN/10mM Ammonium Bicarbonate) to afford the sub-title compound (70 mg) as alight pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.12 (s, 1H), 8.90 (s, 1H),8.87 (s, 1H), 8.29 (d, 1H), 8.16 (d, 1H), 8.12 (d, 1H), 8.10 (s, 1H),7.91-7.83 (m, 1H), 7.74-7.65 (m, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.02(d, 1H), 6.90 (t, 1H), 6.78 (t, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.04(t, 1H), 4.14-4.06 (m, 4H), 4.02-3.94 (m, 2H), 3.81 (s, 3H), 3.71 (dd,2H), 3.65 (s, 3H), 3.64-3.56 (m, 4H), 3.21-3.12 (m, 2H), 1.31 (t, 3H),1.26 (s, 9H), 1.18 (t, 3H).

m/z 860.5 (M+H)+ (ES+).

(v)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-3-(ethylsulfonamido)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (40.7 μL, 0.081 mmol) was added to a solution of thecompound from step (iv) above (70 mg, 0.081 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting solution stirred at rt overnight. Thereaction was quenched with AcOH (24.1 μL, 0.422 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-75% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were neutralised with formic acid andconcentrated to afford the title compound (68 mg) as a light beigesolid.

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H),8.31 (d, 1H), 8.17 (d, 1H), 8.12 (s, 1H), 8.10 (d, 1H), 7.86 (dd, 1H),7.69 (ddd, 1H), 7.60 (ddd, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.86 (t,1H), 6.78 (t, 1H), 6.58 (dd, 1H), 6.09 (d, 1H), 6.03 (t, 1H), 4.01-3.90(m, 4H), 3.81 (s, 3H), 3.73-3.68 (m, 2H), 3.65 (s, 3H), 3.63-3.55 (m,4H), 3.20-3.13 (m, 2H), 1.31 (t, 3H), 1.26 (s, 9H).

m/z 832.5 (M+H)⁺ (ES⁺)

Example 17 2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)isoxazol-3-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

(i) Phenyl (5-(tert-butyl)isoxazol-3-yl)carbamate

A slurry of phenyl chloroformate (0.492 mL, 3.92 mmol,5-(tert-butyl)isoxazol-3-amine (0.5 g, 3.57 mmol) and NaHCO₃ (0.899 g,10.70 mmol) in DCM (8 mL) and THF (2 mL) was stirred at rt for 4 h. Thereaction was diluted with DCM (10 mL), washed with water (10 mL), brine(10 mL) and the solvent evaporated to give a colourless oil that wasstirred in cyclohexane (10 mL) for 10 min. A white solid formed that wascollected by filtration to afford the sub-title compound (674 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.47-7.41 (m, 2H), 7.28 (ddt,1H), 7.25-7.19 (m, 2H), 6.44 (s, 1H), 1.30 (s, 9H).

m/z 261.3 (M+H)⁺ (ES⁺)

(ii) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)isoxazol-3-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetate

Ethyl2-(2-(2-(3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)acetate(see Example 3(ii) above; 100 mg, 0.183 mmol) was dissolved in iPrOAc (2mL) at 50° C. and the product from (i) (62.4 mg, 0.240 mmol) added tothe solution and stirred at 50° C. until the carbamate dissolved (ca 5min). NEt₃ (5.1 μL, 0.037 mmol) was added and the resulting solutionstirred at 75° C. for 4 h. The solvent was removed in vacuo.Chromatography on silica gel (12 g column, 0-5% MeOH/DCM) did not affordsufficient purity and the crude product was further purified bychromatography (RP Flash C18 12 g column, 15-75% MeCN/10 mM AmmoniumBicarbonate) to afford the sub-title compound (86 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.12 (s, 1H), 8.87 (s, 1H),8.18 (d, 1H), 8.11 (d, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.71 (ddd, 1H),7.62 (ddd, 1H), 7.39 (d, 1H), 6.90 (t, 1H), 6.78 (t, 1H), 6.57 (dd, 1H),6.52 (s, 1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.16-4.05 (m, 4H), 4.02-3.95(m, 2H), 3.71 (dd, 2H), 3.65 (s, 3H), 3.64-3.57 (m, 4H), 1.32 (s, 9H),1.19 (t, 3H).

m/z 714.2 (M+H)+ (ES+)

(iii) 2-(2-(2-(3-((4-((4-(3-(5-(tert-Butl)isoxazol-3-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid

NaOH (2M aq.) (175 μL, 0.350 mmol) was added to a solution of thecompound from step (i) above (86 mg, 0.120 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting solution stirred at rt overnight. Thereaction was quenched with AcOH (24.1 μL, 0.422 mmol) and the solventremoved in vacuo. The crude product was purified by chromatography (RPFlash C18 12 g column, 15-75% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were neutralised with formic acid andconcentrated to afford the title compound (59 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.45 (s, 1H), 8.87 (s, 1H),8.21 (t, 1H), 8.11 (d, 1H), 8.03 (d. 1H), 7.87 (dd, 1H), 7.69 (ddd, 1H),7.65-7.55 (m, 1H), 7.37 (d. 1H), 6.77 (s, 1H), 6.73 (t, 1H), 6.60 (dd,1H), 6.52 (s, 1H), 6.09 (d, 1H), 6.03 (t, 1H), 3.96 (s, 2H), 3.89 (d,2H), 3.69 (dd, 2H), 3.65 (s, 3H), 3.62-3.54 (m, 4H), 1.32 (s, 9H) m/z686.5 (M+H)⁺ (ES⁺).

Example 18N-(5-(tert-Butl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-2,5-dihydroisoxazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide

(i)1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-[2-[2-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxo-ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]-4-pyridyl]oxy]-1-naphthyl]urea

To a solution of2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid (see Example 3 above; 500 mg, 0.611 mmol) in DCM (3 mL) and THF (3mL) was added DMAP (74.7 mg, 0.611 mmol). The resulting suspension wascooled to 0° C. and DCC (139 mg, 0.672 mmol) added. The resultingsuspension was stirred at 0° C. for 10 min, then2,2-dimethyl-1,3-dioxane-4,6-dione (26.4 mg, 0.183 mmol) added. Theresulting suspension was stirred at 0° C. for 10 min then at rtovernight. Further portions of DCC (37.8 mg, 0.183 mmol) and2,2-dimethyl-1,3-dioxane-4,6-dione (26.4 mg, 0.183 mmol) were added tothe yellow suspension and stirring continued for 4 h. The solvent wasremoved to afford an orange solid that was suspended in cold DCM (3 mL)and filtered (sinter funnel, Grade 1 Whatman paper), washing with coldDCM (3×2 mL). The filtrate chilled and refiltered through a plug ofcotton wool and solvent was removed affording a light yellow solid. Thecrude product was purified by chromatography on silica gel (12 g column,0-100% EtOAc/isohexane, then 4% MeOH:DCM) to afford the sub-titlecompound (771 mg) as a white solid.

m/z 944.6 (M+H)⁺ (ES⁺)

(ii) Ethyl4-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamidophenyl)ureido-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-3-oxobutanoate

The product from step (i) above (403 mg, 0.324 mmol) was slurried inEtOH (50 mL) and heated to reflux for 24 h. The solvent was removed invacuo to afford a gum that was product was purified by chromatography onsilica gel (40 g column, 0-10% MeOH/DCM,) to afford the sub-titlecompound (200 mg, 0.205 mmol, 63.2% yield) as a colourless gum.

m/z 886.5 (M+H)⁺ (ES⁺)

(iii)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-2,5-dihydroisoxazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide

A suspension of the product from (ii) (100 mg, 0.113 mmol),hydroxylamine hydrochloride (31.3 mg, 0.450 mmol) and sat. aq. sodiumbicarbonate (512 μL, 0.563 mmol) in EtOH (2.5 mL) was heated to refluxfor 1 h, after which time a homogeneous solution was obtained. Thereaction was cooled to rt and concentrated in vacuo. The crude productwas purified by chromatography (RP Flash C18 12 g column, 15-75% MeCN/10mM Ammonium Bicarbonate). The product-rich fractions were combined andthe pH adjusted to 7 with formic acid, the organic solvent wasevaporated under a flow of N₂, protecting the sample from light. Theaqueous solvent was then removed on a rotary evaporator, at 30° C., toafford the title compound (20 mg) as a light pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.02 (s, 1H), 8.94 (s, 1H),8.32 (d, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 8.10 (d, 1H), 7.86 (dd, 1H),7.69 (ddd, 1H), 7.60 (ddd, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.88 (t,1H), 6.78 (t, 1H), 6.58 (dd, 1H), 6.07 (d, 1H), 6.03 (t, 1H), 4.06 (s,2H), 3.95 (dd, 2H), 3.91 (s, 1H), 3.80 (s, 3H), 3.68 (dd, 2H), 3.65 (s,3H), 3.59-3.52 (m, 2H), 3.52-3.44 (m, 2H), 3.09 (s, 3H), 1.27 (s, 9H).

m/z 857.5 (M+H)⁺ (ES⁺)

Example 192-((2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)thio)aceticacid

(i) Methyl 2,2,3,3-tetramethyl-4,7-dioxa-10-thia-3-siladodecan-12-oate

2,2′-Oxydiethanol (7.05 mL, 80.5 mmol), NEt₃ (8.36 mL, 60 mmol) and DMAP(0.020 g, 0.164 mmol) were dissolved in DCM (100 mL) and cooled in anice bath. A solution of TBSCl (7.28 g, 48.3 mmol) in DCM (20 mL) wasadded dropwise over 15 mins and the mixture allowed to warm to roomtemperature overnight. The organic layer was washed with saturatedNaHCO₃ (100 mL), saturated NH₄Cl (100 mL), and then saturated NaCl (100mL), passed through a phase separator and concentrated in vacuo to yielda colourless oil (8.95 g). To a solution of this oil (2.0 g) and NEt₃(1.82 mL, 13.07 mmol) in DCM (20 mL) at 0-5° C. was added MsCl (0.611mL, 7.84 mmol) dropwise. The resulting mixture warmed to rt and stirredfor 2 h, diluted with DCM (30 mL) and the organic layer washed withwater (50 mL), brine (50 mL), passed through a phase separator andconcentrated in vacuo to yield 2.45 g of a light yellow oil. NaH (60% inmineral oil, 0.731 g, 18.27 mmol) was suspended in DMF (10 mL, 129mmol), cooled in an ice bath and methyl 2-mercaptoacetate (1.515 mL,16.60 mmol) added dropwise under nitrogen. After 30 min at rt themixture was cooled in an ice bath and the light yellow oil from above(2.36 g) was added as a solution in DMF (5 mL) and stirred for 2 h. Sat.NH₄Cl(aq) (50 mL) was added and the aqueous layer extracted with EtOAc(2×50 mL). The combined organic layers were washed with brine, dried(Na2SO4), filtered and concentrated in vacuo onto silica gel. The crudeproduct was purified by chromatography on silica gel (80 g column, 0-20%EtOAc/isohexane) to afford the sub-title compound (1.22 g) as acolourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 3.71-3.65 (m, 2H), 3.63 (s, 3H), 3.59 (t,2H), 3.47-3.42 (m, 2H), 3.42-3.37 (m, 2H), 2.74 (t, 2H), 0.86 (s, 9H),0.04 (s, 6H)

(ii) Methyl 2-((2-(2-hydroxyethoxy)ethyl)thio)acetate

The product from step (i) above (546 mg, 1.770 mmol) was dissolved inAcOH:water (3 mL; 2:1 ratio) and stirred at rt for 1 h. The solvent wasthen removed in vacuo to yield the sub-title compound (347 mg) as acolourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.57 (t, 1H), 3.60 (s, 3H), 3.53 (t, 2H),3.48-3.40 (m, 2H), 3.40-3.33 (m, 4H), 2.70 (t, 2H).

(iii) Methyl 2-((2-(2-((methylsulfonyl)oxy)ethoxy)ethyl)thio)acetate

The product from step (ii) above (344 mg, 1.771 mmol) was dissolved inDCM (5 mL) and cooled in an ice bath. NEt₃ (370 μL, 2.66 mmol) followedby MsCl (166 μL, 2.125 mmol) were added dropwise and the mixture left towarm to rt overnight. The mixture was diluted with DCM (10 mL) and theorganic layer washed with 0.1 M HCl (10 mL). The mixture was passedthrough a phase separator and concentrated in vacuo to yield thesub-title compound (396 mg) as light yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.32-4.20 (m, 2H), 3.64-3.61 (m, 2H), 3.60(s, 3H), 3.58 (t, 2H), 3.37 (s, 2H), 3.15 (s, 3H), 2.73 (t, 2H).

(iv) Methyl 2-((2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethyl)thio)acetate

3-Methoxy-5-nitrophenol (118 mg, 0.699 mmol), the product from step(iii) above (200 mg, 0.734 mmol) and potassium carbonate (290 mg, 2.098mmol) were suspended/dissolved in DMF (3 mL) and heated to 80° C.overnight. The reaction was cooled and partitioned between TBME (20 mL)and brine (20 mL). The aqueous layer was extracted with TBME (20 mL) andthe combined organic layers washed with brine (40 mL), dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bychromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) toafford the sub-title compound (170 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.35 (dt, 2H), 7.00 (t, 1H), 4.29-4.15 (m,2H), 3.86 (s, 3H), 3.79-3.73 (m, 2H), 3.66 (t, 2H), 3.63 (s, 3H), 3.42(s, 2H), 2.77 (t, 2H).

m/z 346.0 (M+H)⁺ (ES⁺)

(v) Methyl 2-((2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethyl)thio)acetate

The product from step (iv) above (170 mg, 0.492 mmol) was dissolved inEtOH (4 mL, 68.5 mmol) and H₂O (0.5 mL). Iron (165 mg, 2.95 mmol) andNH₄Cl (211 mg, 3.94 mmol) were added and the flask evacuated andbackfilled with nitrogen three times. The reaction mixture was heated to80° C. with vigorous stirring for 2 h. LCMS revealed complete conversionto the sub-title compound. The mixture was cooled, filtered throughcelite and the solids washed with EtOH (10 mL). The solution wasconcentrated in vacuo to yield the sub-title as a light yellow oil (120mg).

m/z 316.0 (M+H)⁺ (ES⁺)

(vi) Methyl2-((2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-)amino)-5-methoxyphenoxy)ethoxy)ethyl)thio)acetate

A suspension of the product from step (v) above (120 mg, 0.380 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 217 mg, 0.380 mmol), Pd-175 (7.43 mg, 9.51 μmol)and freshly ground potassium carbonate (158 mg, 1.141 mmol) in DMF (3mL) was degassed by 3 cycles of evacuation and backfilling withnitrogen. The reaction was heated to 70° C. (block temperature) for 2 hthen concentrated in vacuo. The crude product was purified bychromatography on RP Flash C18 (26 g column, 25-100% MeCN/10 mM AmmoniumBicarbonate) to afford the sub-title compound (152 mg) as a colourless,glassy solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.16 (s, 1H), 8.93 (s, 1H),8.89 (s, 1H), 8.34-8.26 (m, 1H), 8.19 (d, 1H), 8.12 (d, 1H), 8.10 (d,1H), 7.86 (dd, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.02(d, 1H), 6.90 (t, 1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.07 (d, 1H), 6.03(t. 1H), 4.02-3.94 (m, 2H), 3.81 (s, 3H), 3.74-3.68 (m, 2H), 3.65 (s,3H), 3.62 (s, 3H), 3.41 (s, 2H), 3.10 (s, 3H), 2.77 (t, 2H), 1.27 (s,9H).

m/z 848.0 (M+H)⁺ (ES⁺)

(vii)2-((2-(2-(3-((4-((4-(3-(5-(tert-Butyl-2-methoxy-3-methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)thio)acetic acid

The product from step (vi) (150 mg, 0.177 mmol) was dissolved in THF (4mL). NaOH (2M aq.) (973 μL, 1.946 mmol) was added and the mixturestirred at rt overnight. The reaction was acidified with AcOH (0.25 mL)and concentrated in vacuo. The crude product was purified bychromatography on RP Flash C18 (24 g column, 15-75% MeCN/10 mM AmmoniumBicarbonate). The product containing fractions were combined, acidifiedwith formic acid to ca. pH 4, concentrated in vacuo and the resultingprecipitate filtered off, washed with water (5 mL) and dried in vacuo at50° C. for 24 h to afford the title compound (78 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.40 (s, 1H), 9.17 (s, 1H),8.93 (s, 1H), 8.89 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H),8.10 (d, 1H), 7.86 (dd, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d,1H), 7.02 (d, 1H), 6.90 (t, 1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.07 (d,1H), 6.03 (t, 1H), 4.03-3.93 (m, 2H), 3.80 (s, 3H), 3.74-3.67 (m, 2H),3.67-3.58 (m, 5H), 3.29 (s, 2H), 3.10 (s, 3H), 2.76 (t, 2H), 1.27 (s,9H).

m/z 833.9 (M+H)⁺ (ES⁺)

Example 202-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-oxy)pyridin-2-yl)amino-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid (Enantiomers 1 and 2)

The title compound of Example 14 (40 mg, 0.048 mmol) was submitted topreparative chiral HPLC purification (Gilson, Daicel Chirapak IC column,30% EtOH in 4:1 hexane:DCM (0.2% diethyl amine) to obtain twoenantiontiomers: Enantiomer 1 (9.2 mg) and Enantiomer 2 (5.2 mg). Theabsolute stereochemistry of the two enantiomers is not known.

(a) Enantiomer 1

¹H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.04 (s, 1H), 8.89 (s, 1H),8.33 (d, 1H), 8.15 (d, 1H), 8.13-8.07 (m, 2H), 7.86 (dd, 1H), 7.68 (ddd,1H), 7.59 (ddd, 1H), 7.36 (d, 1H), 7.02 (d, 1H), 6.80-6.71 (m, 2H), 6.58(dd, 1H), 6.10 (d, 1H), 6.02 (t, 1H), 3.93-3.85 (m, 2H), 3.80 (s, 4H),3.68 (dd, 2H), 3.64 (s, 3H), 3.55 (t, 2H), 3.46-3.42 (m, 1H), 3.08 (s,3H), 1.26 (s, 9H), 1.21 (d, 3H).

m/z 832.1 (M+H)⁺

Chiral HPLC (Daicel Chiralpak IC, 5 um, 4.6×250 mm, 45 min method, 1.0mL/imin, 30% EtOH in DCM/Hexane (1:4) (0.2% DEA) RT=8.9 min, 84% ee @254 nm.

(b) Enantiomer 2

¹H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H),8.33 (d, 1H), 8.16 (d, 1H), 8.12 (d, 1H), 8.10 (d, 1H), 7.88-7.84 (m,1H), 7.69 (ddd, 1H), 7.60 (ddd, 1H), 7.37 (d, 1H), 7.02 (d, 1H), 6.81(t, 1H), 6.76 (t, 1H), 6.59 (dd, 1H), 6.10 (d, 1H), 6.03 (t, 1H), 3.92(t, 2H), 3.84 (d, 4H), 3.74-3.67 (m, 2H), 3.65 (s, 3H), 3.56 (t, 2H),3.45-3.42 (m, 1H), 3.09 (s, 3H), 1.27 (s, 9H), 1.23 (d, 3H).

m/z 832.1 (M+H)⁺ (ES⁺)

Chiral HPLC (Daicel Chiralpak IC, 5 urn, 4.6×250 mm, 45 min method, 1.0mL/min, 30% EtOH in DCM/Hexane (1:4) (0.2% DEA) RT=11.2 min, 98% ee @254 nm.

Example 212-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxyethoxy)-2-methylpropanoicacid

(i) Ethyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)-2-methylpropanoate

Ethyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)propanoate (1.1 g, 3.71 mmol) wasdissolved in THF (35 mL) and cooled to −78° C. LiHMDS (1 M in THF, 4.08mL, 4.08 mmol) was added and the reaction stirred for 1 h. MeI (2M inTBME) (2.04 mL, 4.08 mmol) was added and the mixture warmed to rt andstirred overnight. The reaction was quenched with NH₄Cl (2 mL) andconcentrated directly onto silica. The crude product was purified bychromatography on silica gel (80 g column, 0-40% EtOAc/isohexane) toafford the sub-title compound (328 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.17 (m, 5H), 4.50 (s, 2H), 4.11 (q, 2H),3.65-3.53 (m, 6H), 3.53-3.48 (m, 2H), 1.36 (s, 6H), 1.21 (t, 3H).

(ii) Ethyl 2-methyl-2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)propanoate

The product from step (i) above (390 mg, 1.25 mmol) was dissolved inEtOH (30 mL, 1.257 mmol) and 5 wt % Pd—C (type 87 L, 134 mg, 0.063 mmol)added. The mixture was stirred at rt under 4 bar of H₂ for 16 h. HPLCconfirmed consumption of the starting material. The reaction mixture wasfiltered through celite, washing the solids with EtOH (50 mL) andconcentrated in vacuo to yield a colourless oil. The oil was dissolvedin dry DCM (10 mL) and cooled in a water ice bath. NEt₃ (192 μL, 1.378mmol) and MsCl (98 μL, 1.263 mmol) were added and the mixture allowed towarm to rt with stirring overnight. The reaction was diluted with DCM(30 mL), washed with 0.1 M HCl (20 mL) and the aqueous layer furtherextracted with DCM (10 mL). The combined organic layers were passedthrough a phase separator and concentrated in vacuo to afford thesub-title compound (313 mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.34-4.27 (m, 2H), 4.10 (q, 2H), 3.71-3.63(m, 2H), 3.59-3.50 (m, 2H), 3.48-3.40 (m, 2H), 3.18 (s, 3H), 1.32 (s,6H), 1.19 (t, 3H).

(iii) Ethyl2-(2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethoxy)-2-methylpropanoate

3-Methoxy-5-nitrophenol (188 mg, 1.112 mmol), the product from step (ii)above (316 mg, 1.059 mmol) and freshly-ground potassium carbonate (439mg, 3.18 mmol) were suspended in DMF (3 mL) and heated to 80° C.overnight. The reaction was cooled and partitioned between TBME (20 mL)and brine (20 mL). The aqueous layer was extracted with TBME (20 mL) andthe combined organic layers washed with brine (40 mL), dried (MgSO4),filtered and concentrated in vacuo. The crude product was purified bychromatography on silica gel (80 g column, 0-40% EtOAc/isohexane) toafford the sub-title compound (346 mg) as a yellow oil. ¹H NMR (400 MHz,DMSO-d6) δ 7.35 (dt, 2H), 7.00 (t, 1H), 4.26-4.19 (m, 2H), 4.11 (q, 2H),3.86 (s, 3H), 3.80-3.75 (m, 2H), 3.58 (dd, 2H), 3.47 (dd, 2H), 1.33 (s,6H), 1.19 (t, 3H).

(iv) Ethyl2-(2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethoxy)-2-methylpropanoate

The product from step (iii) above (335 mg, 0.902 mmol) was dissolved inEtOH (5 mL) and Pd/C (5 wt % type 87 L, 28.8 mg, 0.014 mmol) added. Thereaction was stirred under 1 bar H₂ for 2 h. The reaction was filteredthrough celite, washing with EtOH (50 mL) and concentrated in vacuo. Thecrude product was purified by chromatography on silica gel (12 g column,0-5% (0.7 M Ammonia/MeOH)/DCM) to afford the sub-title compound (226 mg)as a red oil.

¹H NMR (400 MHz, DMSO-d6) δ 5.78-5.72 (m, 2H), 5.68 (t, 1H), 5.07 (s,2H), 4.11 (q, 2H), 3.99-3.87 (m, 2H), 3.75-3.65 (m, 2H), 3.62 (s, 3H),3.58-3.53 (m, 2H), 3.48-3.43 (m, 2H), 1.33 (s, 6H), 1.19 (d, 3H).

m/z 342.1 (M+H)⁺ (ES⁺)

(v) Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-)oxy)pyridin-2-yl)amino-5-methoxyphenoxy)ethoxyethoxy)-2-methylpropanoate

A suspension of the product from step (iv) above (210 mg, 0.615 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 350 mg, 0.615 mmol) and freshly ground potassiumcarbonate (255 mg, 1.845 mmol) in DMF (3 mL) was degassed by 3 cycles ofevacuation and backfilling with nitrogen. The mixture was heated to 40°C. for 5 min and BrettPhosG3 precatalyst (13.94 mg, 0.015 mmol) wasadded as a solution in DMF (1 mL). The flask was evacuated andbackfilled with nitrogen and then heated to 75° C. (block temperature)for 4 h. The reaction was cooled to rt and a further portion of freshlyground potassium carbonate (255 mg, 1.845 mmol) and Pd-173 (14 mg) wasadded. The reaction was degassed by evacuation and backfilling withnitrogen 3 times and heated to 75° C. (block temperature) for 12 h,diluted with DCM (50 mL), washed with brine (50 mL), passed through aphase separator and concentrated in vacuo. The crude product waspurified by chromatography on RP Flash C18 (40 g column, 25-100% MeCN/10mM Ammonium Bicarbonate) to afford the sub-title compound (77 mg) as abrown solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.90 (d, 2H), 8.31-8.28 (m,1H), 8.19 (d, 1H), 8.14-8.07 (m, 2H), 7.87 (dd, 1H), 7.71 (ddd, 1H),7.61 (ddd, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.91 (t, 1H), 6.78 (t, 1H),6.58 (dd, 1H), 6.07 (d, 1H), 6.03 (t, 1H), 4.10 (q, 2H), 4.01-3.95 (m,2H), 3.81 (s, 3H), 3.74-3.69 (m, 2H), 3.65 (s, 3H), 3.55 (dd, 2H), 3.46(dd, 2H), 3.10 (s, 3H), 1.32 (s, 6H), 1.27 (s, 9H), 1.19 (t, 3H).

m/z 848.0 (M+H)⁺ (ES⁺)

(vi)2-(2-(2-(3-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxyethoxy)-2-methylpropanoicacid

The product from step (v) (77 mg, 0.088 mmol) was dissolved in THF (2mL) and MeOH (0.5 mL). NaOH (2M aq.) (485 μL, 0.969 mmol) was added andthe mixture stirred at rt overnight. The reaction was acidified withAcOH (0.25 mL) and concentrated in vacuo. The crude product was purifiedby chromatography on RP Flash C18 (24 g column, 15-75% MeCN/10 mMAmmonium Bicarbonate). The product containing fractions were combined,acidified with formic acid to ca. pH 4 and concentrated in vacuo. Thesolid was then redissolved in the minimum amount of EtOH (ca. 1 mL) andwater (0.5 mL) added dropwise to crash out the white solid. The vial wasthen centrifuged at 2000 rpm for 2 min and the supernatant decanted toyield the title compound (40 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.38 (s, 1H), 9.11 (s, 1H),8.91 (s, 1H), 8.87 (s, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 8.14-8.07 (m,2H), 7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.02(d, 1H), 6.90 (t, 1H), 6.78 (t, 1H), 6.57 (dd, 1H), 6.08 (d, 1H), 6.03(t, 1H), 3.97 (dd, 2H), 3.81 (s, 3H), 3.71 (dd, 2H), 3.65 (s, 3H), 3.56(dd, 2H), 3.48 (dd, 2H), 3.10 (s, 3H), 1.31 (s, 6H), 1.27 (s, 9H).

m/z 846.1 (M+H)⁺ (ES⁺)

Example 221-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl-1H-pyrazole-4-carboxylicacid

(i) Methyl 1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate

Potassium carbonate (822 mg, 5.95 mmol) was added to a solution of2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (598 mg, 2.181 mmol) andmethyl 1H-pyrazole-4-carboxylate (250 mg, 1.982 mmol) in DMF (15 mL) andheated to 60° C. for 2 days. The reaction was cooled to rt, diluted withEtOAc (50 mL) and washed sequentially with water (30 mL), sat. aq.NaHCO₃ (30 mL) and 20% v/v brine (30 mL). The organic layer was dried(MgSO₄) and concentrated in vacuo. The crude product was purified bychromatography on silica gel (12 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (472 mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (d, 1H), 7.87 (d, 1H), 7.38-7.30 (m,2H), 7.30-7.24 (m, 3H), 4.44 (s, 2H), 4.32 (t, 2H), 3.80 (t, 2H), 3.72(s, 3H), 3.58-3.53 (m, 2H), 3.53-3.48 (m, 2H).

m/z 305.1 (M+H)⁺ (ES⁺)

(ii) Methyl 1-(2-(2-(hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate

Pd/C 10% in 50% paste in water (Type 39) (33.0 mg, 0.310 mmol) was addedto a solution of the product from step (i) above (472 mg, 1.551 mmol) inEtOH (4 mL) and the resulting slurry stirred under H₂ at 1 bar pressureovernight. The reaction was filtered through celite, washing with EtOAc(2×20 mL) and the solvent removed to afford the sub-title compound (326mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (d, 1H), 7.87 (d, 1H), 4.59 (t, 1H),4.31 (t, 2H), 3.78 (t, 2H), 3.74 (s, 3H), 3.48-3.42 (m, 2H), 3.42-3.37(m, 2H).

(iii) Methyl1-(2-(2-(methylsulfonyl)oxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate

MsCl (142 μL, 1.826 mmol) was added to a solution of the product fromstep (ii) above (326 mg, 1.522 mmol) in DCM (10 mL) and TEA (424 μL,3.04 mmol) at 0° C., and the resulting solution stirred at rt overnight.A second aliquot of NEt₃ (424 μL, 3.04 mmol) and MsCl (142 μL, 1.826mmol) was added at rt, and the reaction stirred at rt for further 3 h.The reaction was diluted with DCM (50 mL) and washed with 20% v/v brine(50 mL). The solvent was removed to afford an orange oil. The crudeproduct was purified by chromatography on silica gel (12 g column, 0-10%MeOH/DCM) to afford the sub-title compound (431 mg) as an orange oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (d, 1H), 7.88 (d, 1H), 4.33 (t, 2H),4.27 (m, 2H), 3.83 (t, 2H), 3.74 (s, 3H), 3.65 (dt, 2H), 3.12 (s, 3H).

m/z 293.3 (M+H)⁺ (ES⁺)

(iv) Methyl1-(2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate

Potassium carbonate (611 mg, 4.42 mmol) was added to a solution of3-methoxy-5-nitrophenol (274 mg, 1.622 mmol) and the product from step(iii) above (431 mg, 1.474 mmol) in DMF (15 mL) and heated to 60° C. for2 days. The reaction was cooled to rt, diluted with EtOAc (50 mL) andwashed sequentially with water (30 mL), sat. aq. NaHCO₃ (30 mL) and 20%v/v brine (30 mL). The organic layer was dried (MgSO₄) and concentratedin vacuo. The crude product was purified by chromatography on silica gel(12 g column, 0-100% EtOAc/isohexane) to afford the sub-title compound(387 mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 7.83 (d, 1H), 7.31 (dt, 2H),6.94 (t, 1H), 4.33 (t, 2H), 4.22-4.11 (m, 2H), 3.90-3.82 (m, 5H),3.78-3.72 (m, 2H), 3.71 (s, 3H).

m/z 366.4 (M+H)⁺ (ES⁺)

(v) Methyl1-(2-(2-(3-amino-5-methoxyphenoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate

A slurry of the product from step (iv) above (378 mg, 1.035 mmol), NH₄Cl(22.14 mg, 0.414 mmol) and iron (578 mg, 10.35 mmol) in EtOH (20 mL),water (2 mL) and THF (3 mL) was heated to reflux for 1 h. The reactionwas cooled to rt and filtered through celite, washing with EtOAc (2×20mL). The solvent was removed in vacuo. The crude product was purified bychromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford thesub-title compound (300 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.34 (d, 1H), 7.88 (d, 1H), 5.75 (t, 1H),5.73 (t, 1H), 5.66 (t, 1H), 5.06 (s, 2H), 4.33 (t, 2H), 3.94-3.87 (m,2H), 3.84 (t, 2H), 3.73 (s, 3H), 3.70-3.64 (m, 2H), 3.62 (s, 3H).

m/z 336.3 (M+H)⁺ (ES⁺)

(vi) Methyl1-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino-5-methoxyphenoxy)ethoxy)ethyl-1H-pyrazole-4-carboxylate

A suspension ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 239 mg, 0.420 mmol), the product from step (v)above (141 mg, 0.420 mmol), freshly ground potassium carbonate (174 mg,1.261 mmol) in DMF (2 mL) in a vial was evacuated and back-filled withnitrogen 3 times. The mixture was heated to 40° C. and Pd 175 (9.52 mg,10.51 μmol) added. The reaction mixture was heated at 75° C. for 2 h.The reaction was then cooled and filtered. The filtrate was partitionedbetween EtOAc (50 mL) and 20% v/v brine (50 mL). The organic layer wasdried (MgSO₄), filtered and concentrated. The crude product was purifiedby chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to affordthe sub-title compound (240 mg) as a light brown solid.

m/z 868.1 (M+H)⁺ (ES⁺)

(vii) Methyl1-(2-(2-(3-((4-((4-(3-(5-(tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate

NaOH (2M aq.) (415 μL, 0.830 mmol) was added to a solution of theproduct from step (vi) above (240 mg, 0.277 mmol) in THF (1.6 mL) andMeOH (0.6 mL) and the resulting solution stirred at rt overnight.Further NaOH (2M aq.) (415 μL, 0.830 mmol) was added and the reactionstirred at rt for 2 h. The reaction was quenched with AcOH (24.14 μL,0.422 mmol) and the solvent removed in vacuo. The crude product waspurified by chromatography (RP Flash C18 12 g column, 15-75% MeCN/10 mMAmmonium Bicarbonate) to afford the title compound (130 mg, 0.149 mmol,54.0% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.92 (s, 1H), 8.86 (s, 1H),8.29 (d, 1H), 8.23 (s, 1H), 8.18 (d, 1H), 8.11 (d, 1H), 8.09 (d, 1H),7.87 (dd, 1H), 7.79 (d, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d,1H), 7.02 (d, 1H), 6.87 (t, 1H), 6.80 (t, 1H), 6.57 (dd, 1H), 6.08 (d,1H), 6.02 (t, 1H), 4.32 (t, 2H), 4.00-3.89 (m, 2H), 3.84 (t, 2H), 3.81(s, 3H), 3.73-3.67 (m, 2H), 3.65 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

m/z 854.5 (M+H)⁺ (ES⁺)

Example 23N-(3-(3-(4-((2-((3-(2-(2-(1H-Tetrazol-5-yl)methoxyethoxy)ethoxy)-5-methoxyphenyl)amino)-pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)methanesulfonamide

(i) 2,2,3,3-Tetramethyl-4,7,10-trioxa-3-siladodecane-12-nitrile

A solution of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethanol (2 g,6.35 mmol) in THF (10 mL) was added dropwise to a slurry of NaH (60% inoil, 0.356 g, 8.89 mmol) in dry THF (40 mL) at 0° C. under nitrogen. Theresulting slurry was stirred at 0° C. for 20 min, and a solution ofbromoacetonitrile (0.44 mL, 6.35 mmol) in dry THF (10 mL) added to thereaction mixture. The resulting dark coloured solution was allowed towarm to rt and stirred at rt overnight. The reaction was quenched withMeOH (0.5 mL) and diluted with 20% v/v brine (20 mL) and EtOAc (50 mL).The layers were separated and the aqueous layer extracted with EtOAc(3×20 mL). The combined organic extractions were dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (24 g column, 0-100% EtOAc/isohexane) to afford thesub-title compound (840 mg) as a thick brown oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.44 (s, 2H), 3.65 (dd, 2H), 3.62-3.56 (m,2H), 3.56-3.49 (m, 2H), 3.41 (dd, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

m/z 282 (M+Na)⁺ (ES⁺)

(ii) 2-(2-(2-(Hydroxyethoxy)ethoxy)acetonitrile

The compound from step (i) above (728 mg, 2.81 mmol) was stirred in AcOH(5 mL) and water (2.5 mL) for 1 h. The solvent was removed and theresidue azeotroped with toluene (3×5 mL) to afford the sub-titlecompound (409 mg) as a thick colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.53 (bs, 1H), 4.44 (s, 2H), 3.65-3.57 (m,2H), 3.57-3.49 (m, 2H), 3.49-3.41 (m, 2H), 3.41-3.35 (m, 2H).

(iii) 2-(2-Cyanomethoxy)ethoxy)ethyl methanesulfonate

MsCl (322 μL, 4.14 mmol) was added to a solution of the compound fromstep (ii) above (429 mg, 2.96 mmol) and NEt₃ (824 μL, 5.91 mmol) in DCM(15 mL) at 0° C., then the resulting solution stirred at rt overnight.The reaction was diluted with DCM (50 mL) and washed with 20% v/v brine(100 mL). The organic layer was passed through a hydrophobic frit andconcentrated. The crude product was purified by chromatography on silicagel (12 g column, 0-100% EtOAc/isohexane) to afford the sub-titlecompound (640 mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) 4.50 (s, 2H), 4.39-4.25 (m, 2H), 3.72-3.64 (m,4H), 3.64-3.59 (m, 2H), 3.19 (s, 3H).

(iv) 2-(2-(2-(3-Methoxy-5-nitrophenoxy)ethoxy)ethoxy)acetonitrile

Freshly ground potassium carbonate (1189 mg, 8.60 mmol) was added to asolution of 3-methoxy-5-nitrophenol (533 mg, 3.15 mmol) and the compoundfrom step (iii) above (640 mg, 2.87 mmol) in DMF (15 mL) and heated to60° C. overnight. The reaction was cooled to rt, diluted with EtOAc (100mL) and washed with 20% v/v brine (100 mL). The organic layer was dried(MgSO₄) and concentrated in vacuo. The crude product was purified bychromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (743 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.35 (t, 1H), 7.33 (t, 1H), 7.00 (t, 1H),4.49 (s, 2H), 4.26-4.18 (m, 2H), 3.86 (s, 3H), 3.81-3.72 (m, 2H),3.71-3.59 (m, 4H).

m/z 319.2 (M+Na)⁺ (ES⁺)

(v) 2-(2-(2-(3-Amino-5-methoxyphenoxy)ethoxy)ethoxy)acetonitrile

Iron (754 mg, 13.5 mmol) followed by ammonium chloride (28.9 mg, 0.54mmol) was added to a solution of the compound from step (iv) above (400mg, 1.35 mmol) in EtOH (13 mL), THF (5 mL) and water (2 mL) and theresulting slurry heated to reflux for 2 h. The reaction was cooled andfiltered through celite, washing with EtOAc (2×20 mL). The solvent wasremoved in vacuo. The crude product was purified by chromatography onsilica gel (24 g column, 0-100% EtOAc/isohexane) to afford the sub-titlecompound (263 mg, 0.938 mmol, 69.5% yield) as a thick light yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 5.75 (d, 2H), 5.69 (t, 1H), 5.05 (s, 2H),4.49 (s, 2H), 4.00-3.91 (m, 2H), 3.71-3.63 (m, 6H), 3.63 (s, 3H).

m/z 267.3 (M+H)⁺ (ES⁺)

(vi)N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(2-(2-(cyanomethoxy)ethoxy)ethoxy)-5-methoxyphenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

A suspension ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 310 mg, 0.54 mmol), the compound from step (v)above (145 mg, 0.54 mmol) and freshly ground potassium carbonate (226mg, 1.63 mmol) in DMF (3 mL) was evacuated, back filling with nitrogen 3times. The mixture was heated under nitrogen to 40° C. and Pd-175 (10.6mg, 0.014 mmol) added. The reaction mixture was heated at 75° C. for 2h, cooled and filtered. The filtrate was partitioned between EtOAc (50mL) and 20% v/v brine (50 mL). The organic layer was dried (MgSO₄),filtered and concentrated. The crude product was purified bychromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford athick brown oil. The material was dissolved in DCM (5 mL) and washedwith 20% v/v brine (10 mL). The solvent was removed to afford thesub-title compound (362 mg) as a beige solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H),8.87 (s, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 8.12 (d, 1H), 8.10 (d, 1H),7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.02 (d,1H), 6.91 (t, 1H), 6.79 (t, 1H), 6.58 (dd. 1H), 6.08 (d, 1H), 6.04 (t,1H), 4.48 (s, 2H), 4.04-3.92 (m, 2H), 3.81 (s, 3H), 3.72 (dt, 2H),3.69-3.58 (m, 7H), 3.10 (s, 3H), 1.27 (s, 9H).

m/z 799.4 (M+H)⁺ (ES⁺)

(vii)N-(3-(3-(4-((2-((3-(2-(2-((1H-Tetrazol-5-yl)methoxy)ethoxy)ethoxy)-5-methoxyphenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)-methanesulfonamide

TMSN₃ (49.8 μL, 0.37 mmol) was added to a slurry of the compound fromstep (vi) above (100 mg, 0.12 mmol) and dibutyltin oxide (31 mg, 0.12mmol) in toluene (2 mL) and the resulting slurry heated to 100° C. for 1h. The reaction was cooled to rt and quenched with MeOH (2 mL). Thesolvent was removed and the crude product purified by chromatography (RPFlash C18, 12 g column, 15-75% MeCN/10 mM Ammonium Bicarbonate). Theproduct-rich fractions were combined and the pH adjusted to 7 withformic acid. The solvent was removed to afford an off-white solid. Thiswas dissolved in EtOH (1 mL) and precipitated with water (4 mL). Theresulting precipitate was collected by filtration to afford the titlecompound (31 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H),8.87 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.11 (d, 1H), 8.10 (d, 1H),7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.02 (d,1H), 6.90 (t, 1H), 6.78 (t, 1H), 6.57 (dd. 1H), 6.08 (d, 1H), 6.03 (t,1H), 4.84 (s, 2H), 4.03-3.93 (m, 2H), 3.81 (s, 3H), 3.74-3.68 (m, 2H),3.68-3.58 (m, 7H), 3.10 (s, 3H), 1.27 (s, 9H).

m/z 842.1 (M+H)⁺ (ES⁺)

Example 242-(2-(3-((4-((4-(3-(5-(tert-Buty-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)aceticacid

(i) Ethyl 2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)acetate

Potassium carbonate (1.226 g, 8.87 mmol) was added to a slurry of3-methoxy-5-nitrophenol (0.5 g, 2.96 mmol), ethyl2-(2-chloroethoxy)acetate (0.440 mL, 2.96 mmol) and sodium iodide (0.222g, 1.478 mmol) in DMF (20 mL) and stirred at 70° C. for 2 h. The heatingwas increased to 90° C. and the reaction left to stir for 24 h. Thereaction was cooled to rt and partitioned between EtOAc (100 mL) and 20%v/v brine (100 mL), the organic layer washed with 20% v/v brine (50 mL),dried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby chromatography on silica gel (24 g column, 0-50% EtOAc/isohexane).The material obtained was dissolved in EtOAc (50 mL) and washed withNaOH (2 M aq, 2×50 mL). The organic layer was dried (MgSO₄) andconcentrated in vacuo to afford the sub-title compound (300 mg) as alight yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.40-7.30 (m, 2H), 7.00 (t, 1H), 4.30-4.21(m, 2H), 4.20 (s, 2H), 4.12 (q, 2H), 3.90-3.79 (m, 5H), 1.20 (t, 3H).

m/z 322.2 (M+Na)⁺ (ES⁺)

(ii) Ethyl 2-(2-(3-amino-5-methoxyphenoxy)ethoxy)acetate

Iron (560 mg, 10.0 mmol) followed by ammonium chloride (21.4 mg, 0.40mmol) was added to a solution of the compound from step (i) above (300mg, 1.00 mmol) in EtOH (13 mL), THF (5 mL) and water (2 mL) and theresulting slurry heated to reflux for 1 h and stirred at rt overnight.The reaction was filtered through celite, washing with EtOAc (2×10 mL)and the filtrate concentrated in vacuo. The crude product was purifiedby chromatography on silica gel (24 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (233 mg) as a thick brown oil.

¹H NMR (400 MHz, DMSO-d6) δ 5.75 (p, 2H), 5.68 (t, 1H), 5.05 (br s, 2H),4.17 (s, 2H), 4.12 (q, 2H), 4.00-3.94 (m, 2H), 3.83-3.71 (m, 2H), 3.63(s, 3H), 1.21 (t, 3H).

m/z 270.3 (M+H)⁺ (ES⁺)

Ethyl2-(2-(3-((4-((4-(3-(5-tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxyacetate

A suspension ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 211 mg, 0.37 mmol), the compound from step (ii)above (100 mg, 0.37 mmol) and freshly ground potassium carbonate (154mg, 1.11 mmol) in DMF (3 mL) was evacuated back filling with nitrogen 3times. The mixture was heated under nitrogen to 40° C. and Pd-175 (7.2mg, 9.28 μmol) added. The reaction mixture was heated at 75° C. for 2 h.The reaction was then cooled and filtered. The filtrate was partitionedbetween EtOAc (50 mL) and 20% v/v brine (50 mL). The organic layer wasdried (MgSO₄), filtered and concentrated. The crude product was purifiedby chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to affordthe coupling product as a thick brown oil. The material was dissolved inDCM (5 mL) and washed with 20% v/v brine (10 mL). The solvent wasremoved to afford the sub-title compound (233 mg) as a beige solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H),8.87 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.11 (dd, 2H), 7.87 (dt, 1H),7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.03 (d, 1H), 6.91 (t,1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.03 (t, 1H), 4.18 (s,2H), 4.11 (q, 2H), 4.06-3.96 (m, 2H), 3.85-3.74 (m, 5H), 3.66 (s, 3H),3.10 (s, 3H), 1.27 (s, 9H), 1.19 (t, 3H).

m/z 802.1 (M+H)⁺ (ES⁺)

(iv)2-(2-(3-((4-((4-(3-(5-tert-Butyl-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)aceticacid

NaOH (2M aq, 462 μL, 0.92 mmol) was added to a solution of the compoundfrom step (iv) above (247 mg) in THF (1.6 mL) and MeOH (0.6 mL) and theresulting solution stirred at rt overnight. The reaction was quenchedwith AcOH (106 μL, 1.848 mmol) and the solvent removed in vacuo. Thecrude product was purified by chromatography (RP Flash 018, 12 g column,15-75% MeCN/10 mM Ammonium Bicarbonate) and product rich fractionscombined and the pH adjusted to ca. 7 with formic acid. The solvent wasthen removed to afford a white solid. This was slurried in hot EtOH (2mL), then triturated with water (2 mL). The resulting solid wascollected by filtration, washing with water (2×1 mL) to afford the titlecompound (145 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 9.42 (s, 1H), 9.13 (s, 1H),8.92 (s, 1H), 8.88 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H),8.10 (d, 1H), 7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d,1H), 7.02 (d, 1H), 6.89 (s, 1H), 6.78 (t, 1H), 6.58 (dd, 1H), 6.08 (d,1H), 6.04 (t, 1H), 4.07 (s, 2H), 4.03-3.91 (m, 2H), 3.81 (s, 3H),3.80-3.72 (m, 2H), 3.66 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

m/z 774.4 (M+H)⁺ (ES⁺)

Example 252-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2 amino)-5-methoxyphenoxy)ethoxy)ethoxy)-N—(N,N-dimethylsulfamoyl)acetamide

CDI (26.2 mg, 0.16 mmol) was added to a solution of2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid (see Example 3 above; 120 mg, 0.14 mmol) in dry DMF (2 mL) at rtand the resulting solution stirred at 50° C. for 1 h. Dimethylsulfamide(36.4 mg, 0.293 mmol) and DBU (44.2 μL, 0.293 mmol) were added to thesolution and the reaction stirred at rt overnight. A further portion ofdimethylsulfamide (36.4 mg, 0.293 mmol) and DBU (44.2 μL, 0.293 mmol)was added and the reaction stirred at rt for a further 2 h. The reactionwas quenched with water (0.1 mL) and the crude reaction solutionpurified by chromatography (RP Flash C18, 12 g column, 15-50% MeCN/10 mMAmmonium Bicarbonate). The product rich fractions were combined and thevolatile solvent removed in vacuo. The pH was then adjusted to 7 withformic acid and the resulting solid collected by filtration, washingwith water (2×1 mL), to afford the title compound (48 mg) as a whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.38 (s, 1H), 9.13 (s, 1H),8.91 (s, 1H), 8.87 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H),8.10 (s, 1H), 7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d,1H), 7.03 (d, 1H), 6.91 (t, 1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.08 (d,1H), 6.04 (t, 1H), 4.06 (s, 2H), 4.02-3.94 (m, 2H), 3.81 (s, 3H),3.75-3.69 (m, 2H), 3.66 (s, 3H), 3.61 (s, 4H), 3.10 (s, 3H), 2.80 (s,6H), 1.27 (s, 9H).

m/z 924.5 (M+H)⁺ (ES⁺)

Example 265-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxphenoxy)ethoxy)methyl)thiophene-2-carboxylicacid

(i) Methyl 5-(hydroxymethyl)thiophene-2-carboxylate

Methyl 5-formylthiophene-2-carboxylate (311 mg, 1.82 mmol) was dissolvedin MeOH (4 mL), cooled in an ice bath and NaBH₄ (68 mg, 1.82 mmol) addedportion wise over ten minutes. The reaction was stirred for 2 h afterwhich time sat. aq. ammonium chloride (10 mL) was added. The aqueousphase was extracted with DCM (2×15 mL), passed through a phase separatorand concentrated in vacuo to yield the sub-title compound (303 mg) as acolourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d. 1H), 6.92 (dt, 1H), 4.86-4.69 (m,2H), 3.81 (s, 3H).

(ii) Methyl 5-(chloromethyl)thiophene-2-carboxylate

The product from step (i) (287 mg, 1.66 mmol) was dissolved in dry CHCl₃(3 mL) and cooled to 0° C. DMF (0.05 mL, 3.60 mmol) and thionyl chloride(3 eq, 0.36 mL) were added and the mixture stirred for 2 h. The reactionwas quenched at 0° C. with MeOH (0.5 mL), diluted with DCM (15 mL),washed with brine (15 mL), passed through a phase separator andconcentrated in vacuo. The sub-title compound (303 mg) was isolated ascolourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, 1H), 7.00 (dt, 1H), 4.69 (d, 2H),3.82 (s, 3H).

(iii) Methyl 5-((2-hydroxyethoxy)methyl)thiophene-2-carboxylate

To a stirred solution of dry ethane-1,2-diol (0.35 mL, 6.29 mmol) inDMSO (1.5 mL) at 0° C. was added potassium tert-butoxide (194 mg, 1.73mmol) portion wise over 10 min. The resulting solution was stirred for30 min at same temperature before adding TBAI (58.1 mg, 0.15 mmol). Ahomogeneous solution of the product from step (ii) above (300 mg, 1.57mmol) in DMSO (0.5 mL) was added dropwise to the above reaction mixtureand stirred at rt overnight. MeOH (3 mL) was added and the reactionstirred overnight. Cold water (25 mL) was added and the aqueous layerextracted with ethyl acetate (2×25 mL) and the combined organic layersconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (12 g column, 0-5% MeOH/DCM) to afford the sub-titlecompound (115 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.70 (d, 1H), 7.14 (dt, 1H), 4.78-4.63 (m,3H), 3.81 (s, 3H), 3.58-3.44 (m, 4H).

(iv) Methyl5-((2-((methylsulfonyl)oxy)ethoxy)methyl)thiophene-2-carboxylate

The product from step (iii) above (115 mg, 0.53 mmol) was dissolved inDCM (5 mL) and cooled in an ice bath. NEt₃ (111 μL, 0.79 mmol) followedby MsCl (49.7 μL, 0.63 mmol) were added dropwise and the mixture left towarm to rt overnight. The mixture was diluted with DCM (10 mL) and theorganic layer washed with 0.1 M HCl (10 mL). The mixture was passedthrough a phase separator and concentrated in vacuo to yield thesub-title compound (125 mg) as light yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (d, 1H), 7.19-7.14 (m, 1H), 4.77 (d,2H), 4.41-4.30 (m, 2H), 3.82 (s, 3H), 3.77-3.69 (m, 2H), 3.19 (s, 3H).

(v) Methyl5-((2-(3-Methoxy-5-nitrophenoxy)ethoxy)methyl)thiophene-2-carboxylate

3-Methoxy-5-nitrophenol (65.0 mg, 0.384 mmol), the product from step(iv) above (125 mg, 0.40 mmol) and potassium carbonate (159 mg, 1.15mmol) were suspended/dissolved in DMF (3 mL) and heated to 80° C.overnight. The reaction was cooled and partitioned between TBME (20 mL)and brine (20 mL). The aqueous layer was extracted with TBME (20 mL) andthe combined organic layers washed with brine (40 mL), dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bychromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) toafford the sub-title compound (105 mg) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 7.70 (d, 1H), 7.35 (dt, 2H), 7.15 (dt, 1H),6.99 (t, 1H), 4.79 (d, 2H), 4.36-4.19 (m, 2H), 3.89-3.78 (m, 9H).

(vi) Methyl5-((2-(3-amino-5-methoxyphenoxy)ethoxy)methyl)thiophene-2-carboxylate

The product from step (v) above (105 mg, 0.286 mmol) was dissolved inEtOH (4 mL, 68.5 mmol). Pd—C (type 87 L) (30.4 mg, 0.014 mmol) was addedand the reaction stirred under an atmosphere of hydrogen (1 bar) for 1h. The mixture was filtered through celite and the solids washed withethanol (10 mL). The solution was concentrated directly onto silica. Thecrude product was purified by chromatography on silica gel (12 g column,0-5% (0.7 M Ammonia/MeOH)/DCM) but did not yield a product of sufficientpurity. The product was repurified by chromatography on silica gel (12 gcolumn, 0-5% (0.7 M Ammonia/MeOH)/DCM) to afford the sub-title compound(57 mg) as a dark red oil.

m/z 338.1 (M+H)⁺ (ES⁺)

(vii) Methyl5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxphenoxy)ethoxy)methyl)thiophene-2-carboxylate

N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide(see WO 2014/162126; 96 mg, 0.169 mmol), the product from step (vi)above (57 mg, 0.169 mmol), Pd-175 (6.60 mg, 8.45 μmol) and freshlyground potassium carbonate (70.0 mg, 0.507 mmol) in DMF (2 mL) weredegassed by evacuation and backfilling with nitrogen three times. Theresulting mixture was heated to 70° C. for 2 h after which time afurther portion of Pd-175 (13.2 mg, 8.45 μmol) was added dropwise as asolution in DMF (2 mL) over 2 h. The reaction was cooled andconcentrated in vacuo. The crude product was purified by chromatography(RP Flash C18) (12 g column, 25-100% MeCN/10 mM Ammonium Bicarbonate) toafford the sub-title compound (23 mg) as a dark red solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H),8.87 (s, 1H), 8.32-8.27 (m, 1H), 8.20-8.14 (m, 1H), 8.13-8.06 (m, 2H),7.90-7.84 (m, 1H), 7.74-7.66 (m, 2H), 7.61 (ddd, 1H), 7.38 (d, 1H),7.17-7.11 (m, 1H), 7.03 (d, 1H), 6.90 (t, 1H), 6.80 (t, 1H), 6.58 (dd,1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.77 (d, 2H), 4.03 (dd, 2H), 3.84-3.74(m, 7H), 3.65 (s, 3H), 3.08 (s, 3H), 1.27 (s, 9H).

(viii)5-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methylthiophene-2-carboxylicacid

The product from step (vii) above (22 mg, 0.025 mmol) was dissolved inTHF (0.75 mL) and MeOH (0.25 mL). NaOH (2M aq.) (139 μL, 0.27 mmol) wasadded and the mixture stirred at rt overnight. The reaction wasacidified with AcOH (0.25 mL) and concentrated in vacuo. The crudeproduct was purified by chromatography on RP Flash C18 (12 g column,15-75% MeCN/10 mM Ammonium Bicarbonate). The product-containingfractions were combined, acidified with formic acid to ca. pH 4 andconcentrated in vacuo to yield the title compound (7.8 mg) as a whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.94 (s, 1H), 8.88 (s, 1H),8.30 (d, 1H), 8.18 (d, 1H), 8.14-8.07 (m, 2H), 7.89-7.84 (m, 1H), 7.69(ddd, 1H), 7.60 (ddd, 1H), 7.46 (d, 1H), 7.38 (d, 1H), 7.04 (d, 1H),7.03 (d, 1H), 6.89 (t, 1H), 6.81 (t, 1H), 6.57 (dd, 1H), 6.08 (d, 1H),6.04 (t, 1H), 4.71 (s, 2H), 4.02 (dd, 2H), 3.81 (s, 3H), 3.79-3.73 (m,2H), 3.65 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

m/z 856.2 (M+H)⁺ (ES⁺)

Example 275-((2-(3-((4-((4-(3-(5-tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-3-carboxylicacid

(i) Methyl 5-(hydroxymethyl)thiophene-3-carboxylate

Methyl 5-formylthiophene-2-carboxylate (311 mg, 1.82 mmol) was dissolvedin MeOH (4 mL), cooled to 0° C. and NaBH₄ (114 mg, 2.11 mmol) was addedportionwise over ten minutes. The reaction was stirred for 2 h and sat.aq. ammonium chloride (10 mL) added. The aqueous phase was extractedwith DCM (2×15 mL), passed through a phase separator and concentrated invacuo to yield the sub-title compound (209 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, 1H), 7.40 (dt, 1H), 4.82 (dd, 2H),3.85 (s, 3H), 1.97 (t, 1H).

(ii) Methyl 5-(chloromethyl)thiophene-3-carboxylate

The product from step (i) above (209 mg, 1.21 mmol) was dissolved in dryCHCl₃ (3 mL) and cooled to 0° C. DMF (0.05 mL, 3.60 mmol) and thionylchloride (0.26 mL, 3.6 mmol) were added and the mixture stirred for 2 h.The reaction was quenched at 0° C. with MeOH (0.5 mL). The reaction wasdiluted with DCM (15 mL), washed with brine (15 mL), passed through aphase separator and concentrated in vacuo to yield the sub-titlecompound (190 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=1.4 Hz, 1H), 7.48 (dt, J=1.4, 0.8Hz, 1H), 4.76 (d, J=0.7 Hz, 2H), 3.86 (s, 3H).

(iii) Methyl 5-((2-hydroxyethoxy)methyl)thiophene-3-carboxylate

To a stirred solution of dry ethane-1,2-diol (0.22 mL, 3.99 mmol) inDMSO (1.5 mL) at 0° C. was added potassium tert-butoxide (123 mg, 1.09mmol) portion wise over 10 min. The resulting solution was furtherstirred for 30 min at the same temperature before adding TBAI (36.8 mg,0.10 mmol). A homogeneous solution of the product from step (ii) above(190 mg, 0.99 mmol) in DMSO (0.5 mL) was added dropwise and stirred atrt overnight. MeOH (3 mL) was added and the reaction stirred overnight.Cold water (15 mL) was added, the aqueous layer extracted with ethylacetate (2×25 mL) and the combined organic layers concentrated in vacuo.The crude product was purified by chromatography on silica gel (12 gcolumn, 0-5% MeOH/DCM) to afford the sub-title compound (106 mg) as ayellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.31 (d, 1H), 7.40 (dt, 1H), 4.72-4.62 (m,3H), 3.79 (s, 3H), 3.55-3.49 (m, 2H), 3.49-3.42 (m, 2H).

(iv) Methyl5-((2-((methylsulfonyl)oxy)ethoxy)methyl)thiophene-3-carboxylate

The product from step (iii) above (105 mg, 0.486 mmol) was dissolved inDCM (5 mL) and cooled to 00° C. NEt₃ (102 μL, 0.728 mmol) followed byMsCl (45.4 μL, 0.583 mmol) were added dropwise and the mixture left towarm to rt overnight. The mixture was diluted with DCM (10 mL) and theorganic layer washed with 0.1 M HCl (10 mL). The aqueous layer wasfurther extracted with DCM (5 mL), the combined organic layers passedthrough a phase separator and concentrated in vacuo to yield thesub-title compound (115 mg) as a light yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (d, 1H), 7.45-7.41 (m, 1H), 4.72 (d,2H), 4.47-4.26 (m, 2H), 3.79 (s, 3H), 3.75-3.61 (m, 2H), 3.22-3.09 (m,3H).

(v) Methyl5-((2-(3-methoxy-5-nitrophenoxy)ethoxy))methyl)thiophene-3-carboxylate

3-Methoxy-5-nitrophenol (59.0 mg, 0.349 mmol), the product from step(iv) above (110 mg, 0.366 mmol) and potassium carbonate (145 mg, 1.046mmol) were suspended/dissolved in DMF (3 mL) and heated to 80° C.overnight. The reaction was cooled and partitioned between TBME (20 mL)and brine (20 mL). The aqueous layer was extracted with TBME (20 mL) andthe combined organic layers washed with brine (40 mL), dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bychromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) toafford the sub-title compound (92 mg) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, 1H), 7.45-7.40 (m, 1H), 7.34 (dt,2H), 6.99 (t, 1H), 4.75 (d, 2H), 4.31-4.20 (m, 2H), 3.86 (s, 3H),3.83-3.80 (m, 2H), 3.79 (s, 3H).

(vi) Methyl5-((2-(3-amino-5-methoxyphenoxy)ethoxy)methyl)thiophene-3-carboxylate

The product from step (v) above (92 mg, 0.25 mmol) was dissolved in EtOH(4 mL, 68.5 mmol) with water (0.5 mL). Iron (84 mg, 1.50 mmol) andammonium chloride (107 mg, 2.00 mmol) were added and the reactionmixture heated to 70° C. with vigorous stirring for 2 h. The mixture wascooled, filtered through celite and the solids washed with ethanol (10mL). The solvent was removed in vacuo. The crude product was purified bychromatography on silica gel (12 g column, 0-5% (0.7 MAmmonia/MeOH)/DCM) to afford the sub-title compound (42 mg) as an orangeoil.

¹H NMR (400 MHz, DMSO-d6) δ 8.31 (d, 1H), 7.47-7.40 (m, 1H), 5.79-5.73(m, 2H), 5.69 (t, 1H), 5.05 (s, 2H), 4.73 (d, 2H), 4.06-3.90 (m, 2H),3.79 (s, 3H), 3.76-3.71 (m, 2H), 3.62 (s, 3H).

(vii) Methyl5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-3-carboxylate

A suspension of the product from step (vi) above (37 mg, 0.11 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide (see WO 2014/162126; 62.4 mg, 0.110 mmol), Pd-175(4.28 mg, 5.48 μmol) and freshly ground potassium carbonate (45.5 mg,0.32 mmol) in DMF (3 mL) was degassed by 3 cycles of evacuation andbackfilling with nitrogen. The reaction was heated to 70° C. for 2 h. Afurther portion of Pd-175 (8.48 mg, 10.9 μmol) was added dropwise in DMF(2 mL) over 2 h. The reaction was concentrated in vacuo. The crudeproduct was purified by chromatography on RP Flash C18 (12 g column,25-100% MeCN/10 mM Ammonium Bicarbonate) to afford the sub-titlecompound (36 mg) as a beige solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H),8.87 (s, 1H), 8.36-8.25 (m, 2H), 8.18 (d, 1H), 8.11 (d, 1H), 8.10 (s,1H), 7.89-7.84 (m, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.44-7.40 (m,1H), 7.38 (d, 1H), 7.03 (d, 1H), 6.90 (t, 1H), 6.79 (t, 1H), 6.57 (dd,1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.73 (d, 2H), 4.06-3.99 (m, 2H), 3.81(s, 3H), 3.78 (s, 3H), 3.77-3.72 (m, 2H), 3.65 (s, 3H), 3.10 (s, 3H),1.27 (s, 9H).

(viii)5-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methylthiophene-3-carboxylicacid

The product from step (vii) above (33 mg, 0.038 mmol) was dissolved inTHF (2 mL) and MeOH (0.5 mL). NaOH (2M aq., 209 μL, 0.417 mmol) wasadded and the mixture stirred at rt overnight. The reaction wasacidified with AcOH (0.25 mL) and concentrated in vacuo. The crudeproduct was purified by chromatography on RP Flash C18 (24 g column,15-75% MeCN/10 mM Ammonium Bicarbonate). The product-containingfractions were combined, acidified with formic acid to ca. pH 4,concentrated in vacuo. The resulting solid was redissolved in theminimum amount of ethanol (ca. 0.3 mL) and water (0.2 mL) added dropwiseto crash out the white solid. The vial was centrifuged at 2000 rpm for 5minutes and the supernatant decanted. The resulting solid was dried invacuo at 55° C. for 48 h to yield the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.68 (bs, 1H), 9.38 (s, 1H), 9.12 (bs, 1H),8.91 (s, 1H), 8.87 (s, 1H), 8.29 (d, 1H), 8.20 (d, 1H), 8.19 (d, 1H),8.14-8.07 (m, 2H), 7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H),7.42-7.33 (m, 2H), 7.03 (d, 1H), 6.90 (t, 1H), 6.80 (t, 1H), 6.57 (dd,1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.72 (d, 2H), 4.06-3.98 (m, 2H), 3.81(s, 3H), 3.78-3.71 (m, 2H), 3.65 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

m/z 856.2 (M+H)⁺ (ES⁺)

Example 282-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl-oxy)pyridin-2-yl)amino)-5-(difluoromethoxy)phenoxy)ethoxy)ethoxy)aceticacid

(i) 1-Bromo-3-(difluoromethoxy)-5-nitrobenzene

A mixture of 3-bromo-5-nitrophenol (460 mg, 2.11 mmol), sodium2-chloro-2,2-difluoroacetate (804 mg, 5.28 mmol) and Cs₂CO₃ (1375 mg,4.22 mmol) in DMF (8 mL) was heated at 100° C. for 1 h. The mixture waspartitioned between TBME (50 mL) and water (50 mL), the aqueous layerextracted with TBME (30 mL) and the combined organic layers washed withbrine (50 mL). The organic layer was concentrated in vacuo to yield thesub-title compound (400 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.25 (t, 1H), 7.96 (t, 1H), 7.69-7.62 (m, 1H),6.60 (t, 1H).

(ii) 3-(Difluoromethoxy)-5-nitrophenol

A mixture of KOH (197 mg, 2.98 mmol) and the product from step (i) above(200 mg, 0.746 mmol) in water (1.5 mL) and dioxane (1.5 mL) was degassedfor 5 minutes prior to the addition ofdi-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (17.4mg, 0.041 mmol) and Pd₂(dba)₃ (17.0 mg, 0.019 mmol). The resultingmixture was degassed for a further 2 minutes and then heated under anitrogen atmosphere at 100° C. for 3 h. The reaction was cooled andpartitioned between 1 M HCl (20 mL) and EtOAc (20 mL). The organic layerwas washed with water (20 mL), brine (20 mL), dried (MgSO₄) andconcentrated in vacuo to yield the sub-title compound (176 mg) as a darkbrown oil.

¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, 2H), 6.96 (t, 1H), 6.57 (t, 1H).

(iii) Ethyl2-(2-(2-(3-(difluoromethoxy)-5-nitrophenoxy)ethoxy)ethoxy)acetate

The product from step (ii) above (174 mg, 0.71 mmol), ethyl2-(2-(2-((methylsulfonyl)oxy)-ethoxy)ethoxy)acetate (see Example 2(ii)above; 202 mg, 0.74 mmol) and potassium carbonate (295 mg, 2.13 mmol)were suspended/dissolved in DMF (4 mL) and heated to 60° C. for 16 h.The reaction was cooled and partitioned between TBME (20 mL) and brine(20 mL). The aqueous layer was extracted with TBME (20 mL) and thecombined organic layers washed with brine (40 mL) and concentrated ontosilica gel. The crude product was purified by chromatography on silicagel (12 g column, 0-50% EtOAc/isohexane) to afford the sub-titlecompound (147 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.68-7.61 (m, 1H), 7.61 (t, 1H), 7.45 (t,1H), 7.29 (t, 1H), 4.33-4.24 (m, 2H), 4.17-4.06 (m, 4H), 3.83-3.73 (m,2H), 3.62 (s, 4H), 1.19 (t, 3H).

m/z 397.1 (M+NH₄)⁺ (ES⁺)

(iv) Ethyl2-(2-(2-(3-amino-5-(difluoromethoxy)phenoxy)ethoxy)ethoxy)acetate

A solution of the product from step (iii) above (147 mg, 0.36 mmol) andPd/C (Type 87 L, 5 wt %) (39.2 mg, 0.02 mmol) in EtOH (20 mL) werestirred under 2 bar H₂ for 2 h. The reaction was filtered throughcelite, washing with EtOH (10 mL) and the mixture concentrated in vacuo.The crude product was purified by chromatography on silica gel (12 gcolumn, 0-5% (0.7 M Ammonia/MeOH)/DCM) to afford the sub-title compound(89 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.09 (t, 1H), 5.99 (t, 1H), 5.94 (t, 1H),5.88 (t, 1H), 5.37 (s, 2H), 4.16-4.08 (m, 4H), 4.00-3.95 (m, 2H),3.74-3.67 (m, 2H), 3.66-3.57 (m, 4H), 1.20 (t, 3H).

m/z 350.1 (M+H)⁺ (ES⁺)

(v) Ethyl 2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy)3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(difluoromethoxy)phenoxy)ethoxy)ethoxy)acetate

N-(5-(tert-Butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide (see WO 2014/162126; 128 mg,0.22 mmol), the product from step (iv) above, Pd-175 (8.7 mg, 0.01 mmol)and freshly ground potassium carbonate (93 mg, 0.67 mmol) were dissolvedin DMF (1 mL) and degassed by evacuation and backfilling with nitrogenthree times. The resulting mixture was heated to 70° C. for 2 h. Thereaction mixture was cooled and loaded directly onto a reverse phasecolumn. The crude product was purified by chromatography (RP Flash C18,12 g column, 25-100% MeCN/10 mM Ammonium Bicarbonate) to afford thesub-title compound (116 mg) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.13 (s, 1H), 9.08 (s, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.17 (d, 1H), 8.16-8.09 (m, 2H), 7.90-7.84(m, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.17 (t, 1H),7.14 (t, 1H), 7.08 (t, 1H), 7.03 (d, 1H), 6.63 (dd, 1H), 6.26 (t, 1H),6.08 (d, 1H), 4.14-4.06 (m, 4H), 4.06-3.99 (m, 2H), 3.81 (s, 3H),3.76-3.70 (m, 2H), 3.64-3.57 (m, 4H), 3.09 (s, 3H), 1.27 (s, 9H), 1.18(t, 3H).

m/z 882.3 (M+H)⁺ (ES⁺)

(vi)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(difluoromethoxy)phenoxy)ethoxy)ethoxy)aceticacid

The product from step (v) above (116 mg, 0.13 mmol) was dissolved in THF(3 mL) and MeOH (1 mL). NaOH (2M aq., 723 μL, 1.447 mmol) was added andthe mixture stirred at rt overnight. The reaction was acidified withAcOH (0.25 mL) and concentrated in vacuo. The crude product was purifiedby chromatography on RP Flash C18 (24 g column, 15-75% MeCN/10 mMAmmonium Bicarbonate). The product containing fractions were combined,acidified with formic acid to ca. pH 4, concentrated in vacuo and theresulting precipitate filtered off washing with water (5 mL). The solidwas then redissolved in the minimum amount of ethanol (ca. 1 mL) andwater (0.5 mL) added dropwise to crash out a white solid. The vial wasthen centrifuged at 2000 rpm for 5 minutes and the supernatant decanted.The resulting solid was dried in vacuo at 55° C. for 48 h to yield thetitle compound (58 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.09 (s, 1H), 8.93 (s, 1H),8.30 (d, 1H), 8.18 (d, 1H), 8.14 (d, 1H), 8.11 (d, 1H), 7.86 (dd, 1H),7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.39 (d, 1H), 7.15 (t, 1H), 7.14 (t,1H), 7.08 (t, 1H), 7.03 (d, 1H), 6.63 (dd, 1H), 6.27 (t, 1H), 6.09 (d,1H), 4.08-3.94 (m, 4H), 3.81 (s, 3H), 3.76-3.69 (m, 2H), 3.60 (s, 4H),3.10 (s, 3H), 1.27 (s, 9H).

m/z 854.2 (M+H)⁺ (ES⁺)

Example 292-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl-2-methoxy-3-(methylsulfonamidophenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynylphenoxy)ethoxy)ethoxy)acetic acid

(i) tert-Butyl 2-(2-(2-benzyloxy)ethoxyethoxy)acetate

Sodium hydride (4.08 g, 102 mmol) was added portionwise to an icebath-cooled solution of 2-(2-(benzyloxy)ethoxy)ethanol (9.14 mL, 51.0mmol) in THF (200 mL) over 15 minutes. The reaction was stirred for 1 hafter which time tert-butyl 2-bromoacetate (8.97 mL, 61.1 mmol) in THF(50 mL) was added dropwise over 1 h. The reaction was stirred at icebath temperature for 3 h and quenched with ammonium chloride (50 mL).TBME (250 mL) was added and the organic layer washed with brine (2×200mL). The organic layer was concentrated onto silica and the crudeproduct was purified by chromatography on silica gel (220 g column,0-50% EtOAc/isohexane) to afford the sub-title compound (1.95 g) as acolourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.43-7.20 (m, 5H), 4.50 (s, 2H), 3.99 (s,2H), 3.66-3.47 (m, 8H), 1.42 (s, 9H).

(ii) tert-Butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate

The product from step (i) above (1.83 g, 5.90 mmol) was dissolved inmethanol (30 mL) and Pd—C (type 87 L, 5 wt. %, 0.627 g, 0.29 mmol)added. The mixture was stirred at room temperature under 4 bar ofhydrogen for 16 h. The reaction mixture was filtered through celite,washing the solids with EtOH (50 mL) and concentrated in vacuo to yieldthe sub-title compound (1.23 g) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.57 (t, 1H), 3.99 (s, 2H), 3.60-3.51 (m,4H), 3.51-3.40 (m, 4H), 1.43 (s, 9H).

(iii) tert-Butyl 2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)acetate

The product from step (ii) above (1.23 g, 5.58 mmol) was dissolved inDCM (30 mL) and cooled in an ice bath. EtN₃ (1.16 mL, 8.38 mmol)followed by MsCl (0.52 mL, 6.70 mmol) were added dropwise and themixture left to warm to room temperature overnight. The mixture wasdiluted with DCM (10 mL) and the organic layer washed with 0.1 M HCl (10mL). The mixture was passed through a phase separator and concentratedin vacuo to yield the sub-title compound (1.83 g) as light yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 4.35-4.28 (m, 2H), 4.00 (s, 2H), 3.73-3.65(m, 2H), 3.64-3.54 (m, 4H), 3.18 (s, 3H), 1.43 (s, 9H).

(iv) tert-Butyl 2-(2-(2-(3-bromo-5-nitrophenoxy)ethoxy)ethoxy)acetate

3-bromo-5-nitrophenol (0.626 g, 2.87 mmol), the product from step (iii)above (1 g, 3.02 mmol) and potassium carbonate (1.191 g, 8.62 mmol) weresuspended/dissolved in 3 mL DMF and heated to 80° C. overnight. Thereaction was cooled and partitioned between TBME (20 mL) and brine (20mL). The aqueous layer was extracted with TBME (20 mL) and the combinedorganic layers washed with brine (40 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (40 g column, 0-50% EtOAc/isohexane) to afford thesub-title compound (965 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.04-7.89 (m, 1H), 7.79-7.72 (m, 1H), 7.70(dd, 1H), 4.32-4.22 (m, 2H), 3.99 (s, 2H), 3.82-3.72 (m, 2H), 3.66-3.54(m, 4H), 1.42 (s, 9H).

m/z 439.1 (M+NH₄)⁺ (ES⁺)

(v) tert-Butyl 2-(2-(2-(3-nitro-5-((triisopropylsilyl)ethynyl)phenoxy)ethoxy)ethoxy)acetate

Pd(PPh)₄ (86 mg, 0.075 mmol) was added to a degassed suspension of theproduct from step (iv) above (314 mg, 0.747 mmol), CuI (7.11 mg, 0.037mmol), and ethynyltriisopropylsilane (0.268 mL, 1.195 mmol) intriethylamine (1 mL) and DMF (3 mL). The mixture was heated at 85° C.(block temp.) for 1 h then cooled and concentrated directly onto silicagel. The crude product was purified by chromatography on silica gel (24g column, 0-50% EtOAc/isohexane) to afford the sub-title compound (255mg) as a light yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.82-7.71 (m, 2H), 7.47-7.45 (m, 1H),4.34-4.23 (m, 2H), 3.98 (s, 2H), 3.81-3.73 (m, 2H), 3.66-3.54 (m, 4H),1.41 (s, 9H), 9H), 1.19-1.03 (m, 21H).

(vi) tert-Butyl2-(2-(2-(3-amino-5-((triisopropylsilyl)ethynyl)phenoxy)ethoxy)ethoxy)acetate

The product from step (v) above (255 mg, 0.489 mmol) was dissolved inEtOH (6 mL) and H₂O (0.75 mL). Iron (164 mg, 2.93 mmol) and ammoniumchloride (209 mg, 3.91 mmol) were added and the flask evacuated andbackfilled with nitrogen three times. The reaction mixture was heated to80° C. with vigorous stirring for 2 h. The mixture was cooled, filteredthrough celite and the solids washed with ethanol (10 mL). The resultingcrude product was dissolved in DCM (20 mL), washed with water (20 mL),passed through a phase separator and concentrated in vacuo to yield thesub-title compound (203 mg) as an orange oil.

¹H NMR (400 MHz, DMSO-d6) δ 6.30 (dd, 1H), 6.17 (t, 1H), 6.14 (dd, 1H),5.24 (s, 2H), 4.03-3.96 (nm, 4H), 3.72-3.67 (m, 2H), 3.60 (s, 4H), 1.42(s, 9H), 1.09 (s, 21H).

m/z 492.3 (M+H)⁺ (ES⁺)

(vii) tert-Butyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-Methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-((triisopropylsilyl)ethynyl)phenoxy)ethoxy)-ethoxy)acetate

N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide(see WO 2014/162126; 231 mg, 0.407 mmol), the product from step (vi)above (200 mg, 0.407 mmol), Pd-175 (15.8 mg, 0.02 mmol) and freshlyground potassium carbonate (169 mg, 1.220 mmol) were dissolved/suspendedin DMF (3 mL) and degassed by evacuation and backfilling with nitrogenthree times. The resulting mixture was heated to 70° C. for 2 h. Thereaction mixture was cooled and partitioned between TBME (30 mL) andwater (30 mL). The organic layer was washed with water (20 mL) andconcentrated in vacuo to yield the sub-title compound (152 mg) as abrown solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 9.00 (5, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.15-8.07 (m, 2H), 7.89-7.83(m, 1H), 7.73-7.68 (m, 1H), 7.63-7.58 (m, 1H), 7.56 (t, 1H), 7.39 (d,1H), 7.17 (t, 1H), 7.03 (d, 1H), 6.61 (dd, 1H), 6.48 (dd, 1H), 6.07 (d,1H), 4.10-4.01 (m, 2H), 3.99 (s, 2H), 3.81 (s, 3H), 3.76-3.68 (m, 2H),3.60 (s, 4H), 3.09 (s, 3H), 1.40 (s, 9H), 1.27 (s, 9H), 1.16-1.02 (m,21H).

m/z 1024.3 (M+H)⁺ (ES⁺)

(viii)2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-Methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynylphenoxy)ethoxy)ethoxy)aceticacid

The product from step (vii) above (152 mg, 0.14 mmol) was dissolved inTHF (4 mL) and TBAF (1M in THF) (156 μL, 0.15 mmol) added. The reactionwas stirred for 60 h at room temperature then partitioned between DCM(40 mL) and water (40 mL). The organic layer was washed with brine (50mL), passed through a phase separator and concentrated in vacuo. Thecrude material (100 mg) was dissolved in DCM (1 mL) and TFA (178 μL,2.30 mmol) added. The reaction was stirred for 16 h and a furtherportion of TFA (178 μL, 2.30 mmol) added. The volatiles were removed invacuo and the crude product purified by chromatography (RP Flash C18, 12g column, 15-75% MeCN/10 mM Ammonium Bicarbonate). The product wasfurther purified by preparative HPLC (Basic, Waters X-Bridge Prep-C18, 5μm, 19×50 mm column, 35-65% MeCN in Water) to yield the title compound(6 mg) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.08 (s), 9.08 (s, 1H), 9.04(s, 1H), 8.33 (d, 1H), 8.17 (d, J=2.3 Hz, 1H), 8.15 (d, 1H), 8.10 (d,1H), 7.86 (dd, 1H), 7.69 (ddd, 1H), 7.60 (ddd, 1H), 7.38 (d, 1H), 7.32(t, 1H), 7.26 (s, 1H), 7.02 (d, 1H), 6.63 (dd, 1H), 6.51 (dd, 1H), 6.11(d, 1H), 4.06 (s, 1H), 3.96 (d, 2H), 3.84-3.78 (m, 4H), 3.70 (dd, 2H),3.57 (s, 4H), 3.09 (s, 3H), 1.27 (s, 9H).

m/z 812.2 (M+H)⁺ (ES⁺)

Example 30N-(5-(tert-Butyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

A suspension ofN-(5-(tert-butyl)-3-(3-(4-((2-((3-(2-(2-(cyanomethoxy)ethoxy)ethoxy)-5-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methane-sulfonamide(see Example 23(vi) above; 79 mg, 0.01 mmol) in EtOH (2 mL) andhydroxylamine (50% in water) (6.0 μL, 0.198 mmol) was heated to 75° C.and left to stir overnight. The solvent was removed and the residueazeotroped with toluene (2×1 mL) to afford a clear oil; m/z 832.1 (M+H)⁺(ES⁺). The crude product was dissolved in DMF (2.5 mL) and cooled to 0°C. Pyridine (8.8 μl, 0.109 mmol) was added, followed by isobutylchloroformate (0.013 mL, 0.099 mmol) and the resulting solution stirredat 0° C. for 30 min, then at rt for 20 min. The reaction was quenchedwith water (10 mL) and extracted with EtOAc (3×5 mL). The combinedorganic extractions were washed with brine (5 mL), passed through ahydrophobic frit and concentrated in vacuo to give a brown oil; m/z932.5 (M+H)⁺ (ES⁺). The crude material was dissolved in a mixture ofEtOH (2.5 mL) and sat. aq. NaHCO₃ (0.5 mL) and stirred at 65° C.overnight. The reaction was filtered and diluted with DMF (1 mL). TheEtOH was removed under a flow of air, then the crude reaction mixturewas purified by chromatography on the Companion (RP Flash C18) (12 gcolumn, 15-75% MeCN/10 mM Ammonium Bicarbonate). The product-richfractions were combined and the pH adjusted to ca. 7 with formic acid.The solvent was removed in vacuo to afford a dark brown gum. This wasrepurified by preparative HPLC (Waters, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,30-60% MeCN in Water) and the product-rich fractions freeze-dried toafford the title compound as a colourless gum (5 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H),8.88 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.11 (d, 1H), 8.10 (d, 1H),7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.03 (d,1H), 6.89 (t, 1H), 6.80 (t, 1H), 6.58 (d, 1H), 6.53 (s, 1H), 6.08 (d,1H), 6.04 (t, 1H), 4.34 (s, 2H), 4.03-3.91 (m, 2H), 3.81 (s, 3H),3.74-3.68 (m, 2H), 3.65 (s, 3H), 3.63-3.54 (m, 4H), 3.10 (s, 3H), 1.27(s, 9H).

m/z 857.7 (M+H)⁺ (ES⁺)

Example 312-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid, sodium salt

Method 1

To a 5 L flask under nitrogen was added IPA/water (90:10; 2.56 L, 12volumes), the solvent was heated to 55° C. at which temperature2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid (see Example 3 above: 213.9 g, 0.261 mol) was charged graduallyover 15 minutes. A formal solution was obtained after an additional 7minutes agitation. To the solution (pink) was added sodium hydrogencarbonate (1.05 equiv.; 0.274 mol, 274 mL), maintaining the temperatureat 53° C. The solution was cooled to 50° C. over 20 minutes and seededwith the sodium salt of2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid (1.0 g); the seed maintained and cooling was continued at 10°C./hour to 25° C. after which point 8 volumes of IPA (1.71 L) wascharged over 2 hours. The batch was agitated for 18 hours at thistemperature and then cooled to 0° C. and aged for 1.5 hours ahead ofisolation via filtration. The cake and vessel rinse were performed usingthe batch liquors, the cake pulled dry and the solids dried in vacuo at50° C. for 18 hours. A yield of 81% was obtained (177.9 g) for the titlecompound as a faint red solid; purity by HPLC was reported at 99.24 area% and proton NMR indicated a batch that conformed to structure with0.58% wt IPA and 0.55% wt water (solvents determined by HRGC and KFrespectively). The batch was dried at 50° C. under vacuum to take theIPA level down to 2,238 ppm (0.22%). The sodium content was 2.5% by ionchromatography.

¹H NMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 9.24 (s, 1H), 8.93 (s, 1H),8.38 (d, 1H), 8.08-8.12 (m, 3H), 7.83 (d, 1H), 7.55-7.67 (m, 2H), 7.35(d, 1H), 7.01 (d, 1H), 6.65-6.72 (m, 2H), 6.60 (dd, 1H), 6.11 (d, 1H),6.00 (t, 1H), 3.77-3.84 (m, 5H), 3.63-3.68 (m, 7H), 3.53 (s, 4H), 3.05(s, 3H), 1.25 (s, 9H).

Method 2

Ethyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxyphenoxy)ethoxy)ethoxy)acetate(see Example 3(iii) above; 413 g gross (containing 3.14% ethyl acetate,equivalent to 400 g active, 472.8 mmol, 1 eq.) was mixed withacetone/water (800 mL and 800 mL, 2 vol and 2 vol) and NaOH (37.8 g,945.7 mmol, 2 eq.) and stirred overnight at 22° C. The reaction wasacidified to pH 7.07 (pH range of 6.9 to 7.3 is acceptable) using AcOH(26.6 mL, 465 mmol, 0.9836 eq.), after which IPA (4000 mL, 10 vol) wasadded (though 12 volumes of IPA have been shown to give similar yieldsand purity). The resulting mixture was cooled to 10° C. over 1 h andstirred for 1 h (for larger scale preparations, the mixture can insteadbe stirred overnight at 7° C.) before being filtered to provide a crudeproduct (329 g) 83% yield (for which: purity as determined by LC was98.9%, with <0.1% starting material; XRD and DSC analysis indicated theform as produced by Method 1 above; and NMR analysis indicated 1.3%NaOAc and 0.4% IPA). The crude product (329 g, 392 mmol, 1 eq.) wasslurried in 8 vol of 15% water:IPA (395 mL water:2237 mL IPA) at 22° C.for 2 h. The resulting mixture was then heated to 45° C. for 2 h, beforebeing cooled to 30° C. and then filtered. This gave the title compound(315 g) at 94% recovery from the crude product, for which the NaOAccontent was 0.39% and IPA was 0.36%. The overall yield for the reactionwas 79%.

Example 322-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethoxy)phenoxy)ethoxy)ethoxy)aceticacid

(i) 3-Hydroxy-5-(trifluoromethoxy)benzoic acid

A solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (3200 mg, 11.23mmol) and NaOH (2520 mg, 44.9 mmol) in water (30 mL) and dioxane (30 mL)was degassed for 5 minutes prior to the addition of Pd₂(dba)₃ (206 mg,0.225 mmol) anddi-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (215mg, 0.505 mmol). The resulting mixture was degassed for a further 2minutes and then heated under a nitrogen atmosphere at 100° C. for 2.5h. The mixture was diluted with water (150 mL) and washed with diethylether (3×75 mL). The aqueous layer was then acidified with HCl (1 M, 33mL) to ˜pH 3 and extracted with ethyl acetate (3×75 mL). The combinedorganic layers were washed with saturated brine (50 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure to afford ayellow oil. The oil was redissolved in diethyl ether (10 mL) and dilutedwith isohexane (30 mL). The resulting precipitate was collected byfiltration and washed with isohexane (10 mL) to yield the sub-titlecompound (1.71 g) as a tan solid.

¹H NMR (400 MHz, DMSO-d6) δ 13.34 (bs, 1H), 10.57 (bs, 1H), 7.36 (dd,1H), 7.28-7.20 (m, 1H), 6.99-6.90 (m, 1H).

(ii) Benzyl3-(2-(2-(2-(tert-butoxy)-2-oxoethoxy)ethoxy)ethoxy)-5-(trifluoromethoxy)benzoate

The product from step (i) above (210 mg, 0.945 mmol) and potassiumcarbonate (392 mg, 2.84 mmol) was dissolved/suspended in DMF (1.25 mL)and benzyl bromide (0.112 mL, 0.945 mmol) added. The mixture was stirredat room temperature for 4 h. Potassium carbonate (392 mg, 2.84 mmol),DMF (4 mL) and tert-butyl2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)acetate (see Example 29(iii)above; 310 mg, 1.040 mmol) were added and the reaction heated to 70° C.for 16 h. The reaction was cooled and partitioned between TBME (50 mL)and water (50 mL). The aqueous layer was extracted with DCM (50 mL), thecombined organic layers washed with brine (50 mL) and concentrated invacuo. The crude product was purified by chromatography on silica gel(12 g column, 0-50% EtOAc/iso-hexane) to afford the sub-title compound(278 mg) as a colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, 1H), 7.50-7.45 (m, 2H), 7.45-7.34(m, 4H), 7.34-7.29 (m, 1H), 5.38 (s, 2H), 4.28-4.17 (m, 2H), 3.98 (s,2H), 3.82-3.72 (m, 2H), 3.65-3.55 (m, 4H), 1.40 (s, 9H).

m/z 532.2 (M+NH₄)⁺ (ES⁺)

(iii)3-(2-(2-(2-(tert-Butoxy)-2-oxoethoxy)ethoxy)ethoxy)-5-(trifluoromethoxy)benzoicacid

The product from step (ii) above (278 mg, 0.540 mmol) and Pd—C (57.5 mg,0.027 mmol) were dissolved/suspended in EtOH (10 mL) and stirred underan atmosphere of H₂ (2 bar) for 16 h. The reaction was filtered andconcentrated in vacuo to yield the sub-title compound (214 mg) as aglassy solid.

¹H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 7.48 (dd, 1H), 7.42-7.34 (m,1H), 7.26-7.20 (m, 1H), 4.26-4.18 (m, 2H), 3.99 (s, 2H), 3.82-3.71 (m,2H), 3.66-3.54 (m, 4H), 1.41 (s, 9H).

(iv) tert-Butyl2-(2-(2-(3-(((benzyloxy)carbonyl)amino)-5-(trifluoromethoxy)phenoxy)ethoxy)-ethoxy)acetate

NEt₃ (0.071 ml, 0.513 mmol) was added to a stirred solution of benzylalcohol (0.355 mL, 3.42 mmol), the product from step (iii) above (145mg, 0.342 mmol) and diphenyl phosphorylazide (0.081 mL, 0.376 mmol) intoluene (2 mL, 0.342 mmol). The reaction was heated to 80° C. for 2 hand concentrated in vacuo. The crude product was purified bychromatography on silica gel (4 g column, 0-50% EtOAc/isohexane) toafford the sub-title compound (53 mg) as a colourless oil.

m/z 547.2 (M+NH₄)⁺ (ES⁺)

(v) tert-Butyl2-(2-(2-(3-amino-5-(trifluoromethoxy)phenoxy)ethoxy)ethoxy)acetate

The product from step (iv) above (50 mg, 0.094 mmol) and Pd—C (20.1 mg,9.44 μmol) was dissolved/suspended in EtOH (10 mL) and stirred under anatmosphere of H₂ (2 bar) for 16 h. The reaction was cooled, filteredthrough celite, washing with EtOH (10 mL) and concentrated in vacuo toyield the sub-title compound (38 mg) as a red oil.

m/z 396.1 (M+H)⁺ (ES⁺)

(vi) tert-Butyl2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethoxy)phenoxy)ethoxy)ethoxy)-acetate

N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide(see WO 2014/162126; 54.7 mg, 0.096 mmol), the product from step (v)above (38 mg, 0.096 mmol), Pd-175 (7.51 mg, 9.61 μmol) and freshlyground potassium carbonate (39.8 mg, 0.288 mmol) were degassed byevacuation and backfilling with nitrogen three times. The resultingmixture was heated to 70° C. for 2 h. The reaction mixture was cooledand injected directly onto a RP column. The crude product was purifiedby chromatography (RP Flash C18, 12 g column, 25-100% MeCN/10 mMAmmonium Bicarbonate) to afford the sub-title compound (52 mg) as alight yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.19 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.16 (d, 1H), 8.12 (d, 1H),7.86 (dd, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.40 (d, 1H), 7.31 (s,1H), 7.28 (t, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.40 (t, 1H), 6.07 (d,1H), 4.07-4.02 (m, 2H), 3.98 (s, 2H), 3.81 (s, 3H), 3.76-3.71 (m, 2H),3.59 (s, 4H), 3.10 (s, 3H), 1.40 (s, 9H), 1.27 (s, 9H).

(vii)2-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethoxy)phenoxy)ethoxy)ethoxy)aceticacid

The product from step (vi) above (50 mg, 0.054 mmol) was dissolved inTHF (1 mL) and NaOH (2 M aq, 269 μL, 0.539 mmol) added. The mixture wasstirred overnight and then acidified to pH 4 with AcOH (0.25 mL) andconcentrated in vacuo. The crude product was purified by chromatography(RP Flash C18, 4 g column, 35-65% MeCN/10 mM Ammonium Bicarbonate), theproduct containing fractions were acidified to pH 4 with formic acid(0.6 mL) and concentrated in vacuo to afford the title compound (20 mg)as a light beige solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.23 (s, 1H), 9.02 (s, 1H),8.33 (d, 1H), 8.17 (d, 1H), 816 (d, 1H), 8.11 (d, 1H), 7.86 (dd, 1H),7.69 (ddd, J=8.4, 1H), 7.60 (ddd, 1H), 7.39 (d, 1H), 7.33 (s, 1H), 7.24(t, 1H), 7.03 (d, 1H), 6.65 (dd, 1H), 6.42-6.39 (m, 1H), 6.10 (d, 1H),4.03 (dd, 2H), 3.84 (s, 2H), 3.81 (s, 3H), 3.75-3.68 (m, 2H), 3.58 (s,4H), 3.09 (s, 3H), 1.27 (s, 9H).

m/z 872.2 (M+H)⁺ (ES⁺)

Example 33N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((3-oxo-2,3-dihydroisoxazol-5-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

A slurry of ethyl4-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-3-oxobutanoate(see Example 18(ii) above; 359 mg, 0.404 mmol) in MeOH (3.5 mL) andwater (0.5 mL) was cooled to 0° C. and NaOH (2 M aq) (404 μL, 0.809mmol) was added. The resulting solution was stirred at 0° C. for 10 min.A solution of hydroxylamine hydrochloride (84 mg, 1.213 mmol) in MeOH(200 μL) was prepared and cooled to 0° C. NaOH (2 M aq) (606 μL, 1.213mmol) was added to the hydroxylamine solution, and stirred at 0° C. for10 min. The hydroxylamine solution was then added to the solution ofenolate and stirred at 0° C. for 2 h. The solution was then addeddropwise to conc HCl (100 μL, 3.29 mmol) at 75° C., and stirred at 75°C. for 1 h. The heating was removed and the pH was adjusted to ca 7 withNaOH (2 M aq.) and diluted with water (20 mL). The aqueous layer wasextracted with EtOAc (3×10 mL) and the combined organic extracts washedwith 20% v/v brine (10 mL). The organic layer was passed through ahydrophobic frit and concentrated in vacuo. The crude product waspurified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate),Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN inWater) and the product rich fractions freeze dried to afford the titlecompound (38 mg) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.94 (s, 1H), 8.70 (s, 1H),8.34 (d, 1H), 8.13-8.05 (m, 2H), 7.84 (d, 1H), 7.67 (ddd, 1H), 7.63-7.54(m, 2H), 7.36 (d, 1H), 7.03 (d, 1H), 6.91-6.84 (m, 2H), 6.56 (dd, 1H),6.09 (d, 1H), 6.04 (t, 1H), 4.05 (s, 1H), 4.00-3.94 (m, 2H), 3.84 (s,1H), 3.78 (s, 3H), 3.73-3.67 (m, 2H), 3.66 (s, 3H), 3.59-3.54 (m, 2H),3.52-3.47 (m, 2H), 2.61 (s, 3H), 1.22 (s, 9H).

m/z 857.2 (M+H)⁺ (ES⁺)

Example 34 5-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl-1-methyl-1H-pyrrole-2-carboxylicacid

(i) Methyl 5-(hydroxymethyl)-1-methyl-1H-pyrrole-2-carboxylate

Sodium borohydride (0.249 g, 6.58 mmol) was added to a solution ofmethyl 5-formyl-1-methyl-1H-pyrrole-2-carboxylate (1.1 g, 6.58 mmol) ina mixture of MeOH (50 mL) and THF (15 mL) at 0° C. and the resultingsolution stirred at 0° C. for 2 h. The reaction was slowly quenched withsat. aq. ammonium chloride (50 mL) and a white solid crashed out. Thesolution was filtered, and the filtrate extracted with DCM (2×50 mL).The solvent was removed in vacuo. The crude material was dissolved inDCM (2 mL) and passed through a plug of silica, washing with 5% MeOH inDCM (200 mL). The solvent was removed in vacuo to afford the sub-titlecompound as a brown oil (1.12 g).

m/z 170.6 (M+H)⁺ (ES⁺)

(ii) Methyl5-((2-(benzyl)oxy)ethoxy)methyl-1-methyl-1H-pyrrole-2-carboxylate

NaH (60% in oil, 213 mg, 5.32 mmol) was added in two portions over 5 minto a solution of the compound from step (i) above (600 mg, 3.55 mmol),((2-bromoethoxy)methyl)benzene (0.6 mL, 3.79 mmol) and sodium iodide(532 mg, 3.55 mmol) in dry DMF (50 mL) under nitrogen at 0° C., and theresulting solution stirred at rt overnight. The reaction was quenchedwith MeOH (3 mL) then diluted with 20% v/v brine (100 mL). The aqueouslayer was extracted with EtOAc (3×100 mL), and the combined organicextractions washed with 20% v/v brine (50 mL). The organic layer wasdried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (213 mg) as a thin colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.39-7.24 (m, 5H), 6.80 (d, 1H), 6.15 (d,1H), 4.51 (s, 2H), 4.48 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.65-3.49(m, 4H).

m/z 304.1 (M+H)⁺ (ES⁺)

(iii) Methyl5-((2-hydroxyethoxy)methyl)-1-methyl-1H-pyrrole-2-carboxylate

Pd/C 10% in 50% paste in water (Type 39) (14.94 mg, 0.140 mmol) wasadded to a solution of the compound from step (ii) above (213 mg, 0.702mmol) in EtOH (4 mL) and the resulting slurry stirred under hydrogen at1 bar pressure for 4 h. The reaction was filtered through celite,washing with EtOAc (20 mL) and the solvent removed to afford thesub-title compound (137 mg) as a thin colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 6.80 (d, 1H), 6.16 (d, 1H), 4.63 (t, 1H),4.49 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.54-3.47 (m, 2H), 3.47-3.41(m, 2H).

m/z 236.1 (M+Na)⁺ (ES⁺)

(iv) Methyl5-((2-(3-methoxy-5-nitrophenoxy)ethoxy)methyl)-1-methyl-1H-pyrrole-2-carboxylate

DIAD (339 μL, 1.745 mmol) was added to a solution of the compound fromstep (iii) above (310 mg, 1.454 mmol), 3-methoxy-5-nitrophenol (295 mg,1.745 mmol) and triphenylphosphine (458 mg, 1.745 mmol) in dry THF (15mL) at 0° C., and the resulting red solution stirred at rt overnight.The yellow solution was diluted with EtOAc (30 mL) and washed with water(20 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo.The crude product was purified by chromatography on the Companion (40 gcolumn, 0-100% EtOAc/isohexane) to afford the desired Mitsunobu productas a yellow solid. The product was dissolved in EtOAc (50 mL) and washedsequentially with NaOH (2 M aq., 2×50 mL), water (50 mL) and 20% v/vbrine (50 mL). The organic layer was dried (MgSO₄) and concentrated invacuo to afford the sub-title compound (638 mg) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 7.33 (m, 2H), 6.96 (t, 1H), 6.79 (d, 1H),6.18 (d, 1H), 4.57 (s, 2H), 4.30-4.17 (m, 2H), 3.85 (s, 3H), 3.83 (s,3H), 3.79-3.74 (m, 2H), 3.73 (s, 3H).

m/z 387.1 (M+Na)⁺ (ES⁺)

(v) Methyl5-((2-(3-amino-5-methoxyphenoxy)ethoxy)methyl)-1-methyl-1H-pyrrole-2-carboxylate

Iron powder (978 mg, 17.51 mmol) followed by ammonium chloride (37.5 mg,0.700 mmol) was added to a solution of the compound from step (iv) above(638 mg, 0.841 mmol) in EtOH (13 mL), THF (5 mL) and water (2 mL) andthe resulting slurry heated to reflux for 2 h. The reaction was cooledand filtered through celite, washing with EtOAc (2×20 mL). The solventwas removed in vacuo. The crude product was purified by chromatographyon silica gel (24 g column, 0-100% EtOAc/isohexane) to afford thesub-title compound (238 mg) as a thick colourless oil.

¹H NMR (400 MHz, DMSO-d6) δ 6.80 (d, 1H), 6.18 (d, 1H), 5.75 (m, 2H),5.67 (t, 1H), 5.05 (s, 2H), 4.55 (s, 2H), 3.99-3.93 (m, 2H), 3.85 (s,3H), 3.74 (s, 3H), 3.71-3.65 (m, 2H), 3.62 (s, 3H).

m/z 335.0 (M+H)⁺ (ES⁺)

(vi) Methyl5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-methylsulfonamido)phenyl)ureido)-naphthalen-1-)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl-1-methyl-1H-pyrrole-2-carboxylate

A suspension ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see WO 2014/162126; 405 mg, 0.712 mmol), the compound from step (v)above (238 mg, 0.712 mmol), freshly ground potassium carbonate (295 mg,2.135 mmol) in DMF (3 mL) was evacuated back filling with nitrogen 3times. The mixture was heated under nitrogen to 40° C. and Pd-175 (13.90mg, 0.018 mmol) added. The reaction mixture was heated at 75° C. for 2h. The reaction was then cooled and filtered. The filtrate waspartitioned between EtOAc (50 mL) and 20% v/v brine (50 mL). The organiclayer was passed through a hydrophobic frit then concentrated. The crudeproduct was purified by chromatography (RP Flash C18) (24 g column,15-80% MeCN/10 mM Ammonium Bicarbonate) to afford the sub-title compound(350 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H),8.87 (s, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 8.11 (d, 1H), 8.10 (d, 1H),7.87 (dt, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d, 1H), 7.03 (d,1H), 6.89 (t, 1H), 6.86-6.77 (m, 2H), 6.58 (dd, 1H), 6.17 (d, 1H), 6.08(d, 1H), 6.02 (t, 1H), 4.55 (s, 2H), 4.07-3.95 (m, 2H), 3.84 (s, 3H),3.81 (s, 3H), 3.73 (s, 3H), 3.72-3.69 (m, 2H), 3.65 (s, 3H), 3.10 (s,3H), 1.27 (s, 9H).

m/z 867.3 (M+H)⁺ (ES⁺)

(vii)5-((2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethoxyphenoxy)ethoxy)methyl)-1-methyl-1H-pyrrole-2-carboxylicacid

NaOH (2M aq) (606 μl, 1.211 mmol) was added to a solution of thecompound from step (vi) above (350 mg, 0.404 mmol) in THF (3 mL) andMeOH (1.2 mL) and the resulting solution stirred at rt for 8 h. Afurther portion of NaOH (2M aq) (606 μL, 1.211 mmol) was added and theresulting solution stirred at rt overnight. The solution was quenchedwith AcOH (139 μL, 2.422 mmol) and the solvent removed in vacuo. Thecrude product was purified by chromatography (RP Flash 018) (12 gcolumn, 15-75% MeCN/10 mM Ammonium Bicarbonate). The product richfractions were combined and the pH adjusted to 7 with formic acid. Thevolatile solvent was removed in vacuo during which a solid crashed out.This was collected by filtration, washing with water (2×2 mL) and thesolid dried in vacuo at 40° C. overnight to afford the title compound(165 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.38 (s, 1H), 9.13 (s, 1H),8.91 (s, 1H), 8.87 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H),8.10 (d, 1H), 7.87 (dd, 1H), 7.70 (ddd, 1H), 7.61 (ddd, 1H), 7.38 (d,1H), 7.03 (d, 1H), 6.90 (t, 1H), 6.79 (t, 1H), 6.74 (d, 1H), 6.57 (dd,1H), 6.13 (d, 1H), 6.08 (d, 1H), 6.03 (t, 1H), 4.53 (s, 2H), 4.06-3.93(m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.75-3.68 (m, 2H), 3.65 (s, 3H),3.10 (s, 3H), 1.27 (s, 9H).

m/z 853.0 (M+H)⁺ (ES⁺)

Biological Testing: Experimental Methods

Enzyme Binding Assays (Kinomescan)

Kinase enzyme binding activities of compounds disclosed herein may bedetermined using a proprietary assay which measures active site-directedcompetition binding to an immobilized ligand (Fabian, M. A. et al.,Nature Biotechnol., 2005, 23:329-336). These assays may be conducted byDiscoverX (formerly Ambit; San Diego, Calif.). The percentage inhibitionproduced by incubation with a test compound may be calculated relativeto the non-inhibited control.

Enzyme Inhibition Assays

The enzyme inhibitory activities of compounds disclosed herein aredetermined by FRET using synthetic peptides labelled with both donor andacceptor fluorophores (Z-LYTE, Invitrogen Ltd., Paisley, UK).

p38 MAPKα Enzyme Inhibition

The following two assay variants can be used for determination of p38MAPKα inhibition.

Method 1

The inhibitory activities of test compounds against the p38 MAPKαisoform (MAPK14: Invitrogen) are evaluated indirectly by determining thelevel of activation/phosphorylation of the down-stream molecule,MAPKAP-K2. The p38 MAPKα protein (80 ng/mL, 2.5 μL) is mixed with thetest compound (2.5 μL of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL or 0.004μg/mL) for 2 hr at RT. The mix solution (2.5 μL) of the p38α inactivetarget MAPKAP-K2 (Invitrogen, 600 ng/mL) and FRET peptide (8 μM; aphosphorylation target for MAPKAP-K2) is then added, then the kinasereaction is initiated by adding ATP (40 μM, 2.5 μL). The mixture isincubated for 1 hr at RT. Development reagent (protease, 5 μL) is addedfor 1 hr prior to detection in a fluorescence microplate reader(Varioskan® Flash, ThermoFisher Scientific).

Method 2

This method follows the same steps as Method 1 above, but utilises ahigher concentration of the p38 MAPKα protein (2.5 μL of 200 ng/mLprotein instead of 2.5 μL of 80 ng/mL protein) for mixing with the testcompound (tested at either 1 μg/mL, 0.1 μg/mL, 0.01 μg/mL or 0.001μg/mL).

p38 MAPKγ Enzyme Inhibition

The inhibitory activities of compounds of the invention against p38MAPKγ(MAPK12: Invitrogen), are evaluated in a similar fashion to thatdescribed hereinabove. The enzyme (800 ng/mL, 2.5 μL) is incubated withthe test compound (2.5 μL of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or0.004 μg/mL) for 2 hr at RT. The FRET peptides (8 μM, 2.5 μL), andappropriate ATP solution (2.5 μL, 400 μM) are then added to theenzymes/compound mixtures and the whole is incubated for 1 hr.Development reagent (protease, 5 μL) is added for 1 hr prior todetection in a fluorescence microplate reader (Varioskan® Flash, ThermoScientific).

c-Src and Syk Enzyme Inhibition

The inhibitory activities of compounds of the invention against c-Srcand Syk enzymes (Invitrogen), are evaluated in a similar fashion to thatdescribed hereinabove. The relevant enzyme (3000 ng/mL or 2000 ng/mLrespectively, 2.5 μL) is incubated with the test compound (either 1μg/mL, 0.1 μg/mL, 0.01 μg/mL, or 0.001 μg/mL, 2.5 μL each) for 2 hr atRT. The FRET peptides (8 μM. 2.5 μL), and appropriate ATP solutions (2.5μL, 800 μM for c-Src, and 60 μM ATP for Syk) are then added to theenzymes/compound mixtures and the mixture incubated for 1 hr.Development reagent (protease, 5 μL) is added for 1 hr prior todetection in a fluorescence microplate reader (Varioskan® Flash,ThermoFisher Scientific).

GSK 3α Enzyme Inhibition

The following two assay variants can be used for determination of GSK 3αinhibition.

Method 1

The inhibitory activities of compounds of the invention against the GSK3α enzyme isoform (Invitrogen), are evaluated by determining the levelof activation/phosphorylation of the target peptide. The GSK3-α protein(500 ng/mL, 2.5 μL) is mixed with the test compound (2.5 μL at either 4μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL) for 2 hr at RT. The FRETpeptide (8 μM, 2.5 μL), which is a phosphorylation target for GSK3α, andATP (40 μM, 2.5 μL) are then added to the enzyme/compound mixture andthe resulting mixture incubated for 1 hr. Development reagent (protease,5 μL) is added for 1 hr prior to detection in a fluorescence microplatereader (Varioskan® Flash, ThermoFisher Scientific).

In all cases, the site-specific protease cleaves non-phosphorylatedpeptide only and eliminates the FRET signal. Phosphorylation levels ofeach reaction are calculated using the ratio of coumarin emission(donor) over fluorescein emission (acceptor), for which high ratiosindicate high phosphorylation and low ratios indicate lowphosphorylation levels. The percentage inhibition of each reaction iscalculated relative to non-inhibited control and the 50% inhibitoryconcentration (IC₅₀ value) is then calculated from theconcentration-response curve.

Method 2

This method follows the same steps as Method 1 above, but utilises ashorter period of mixing of the test compound (105 minutes instead of 2hours) with the GSK3-α protein. In addition, the concentrations of testcompound employed are either 10 μg/mL, 1 μg/mL, 0.1 μg/mL, or 0.01 μg/mL

Cellular Assays

The compounds of the invention were studied using one or more of thefollowing assays.

(a) Inhibition of p38 MAPKα and Lck in Jurkat Cells

Jurkat T cells were cultured in starve medium (RPMI 1640+5% FBS) for 24h prior to the experiment. Cells were harvested and resuspended at10×10⁶ cells/mL in starve medium and then plated into round-bottomed 96well plates at 1×10⁶ cells/well. Serial dilutions of test compound wereadded (1% final DMSO concentration) for 2 h prior to stimulation.Following pre-incubation with compound, cells were stimulated with H₂O₂(0.05% final) for 5 min. The reaction was stopped by centrifugation at2000 rpm (3 min, 4° C.), then the supernatant was removed and 100 μL ofcold fix/perm solution (BD Fix/Perm kit #554714) added. Plates wereincubated for 20 min at 4° C. before centrifugation and washing withsupplied 1× wash medium (BD Fix/Perm kit #554714). Cells were stainedfor either phospho-p38α (T180/182), supplied by Cell SignallingTechnology (9211s), or phospho-Lck (Y394), supplied by R&D (MAB7500).Antibodies were diluted to 5 μg/mL (R&D) or 1:200 (Cell SignallingTechnology) in wash medium, before being incubated 1 h at 4° C. in thedark. Following 3 repeat washes with ice cold wash buffer, secondaryantibody (anti-rabbit-FITC #F1362 or anti-mouse-FITC #F2883, both fromSigma) was added at a dilution of 1:1000 and incubated for 1 h at 4° C.in the dark. Cells were washed 3× times in cold wash buffer then,following a final wash in cold PBS, were resuspended in 150 μL cold PBS.Cells were analysed by flow cytometry using BD Accuri C6.

(aa) LPS-Induced TNFα/IL-8 Release in d-U937 Cells

U937 cells, a human monocytic cell line, are differentiated tomacrophage-type cells by incubation with phorbol myristate acetate (PMA;100 ng/mL) for 48 to 72 hr. Cells are pre-incubated with finalconcentrations of test compound for 2 hr and are then stimulated with0.1 μg/mL of LPS (from E. Coli: 0111:B4, Sigma) for 4 hr. Thesupernatant is collected for determination of TNFα and IL-8concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibitionof TNFα production is calculated as a percentage of that achieved by 10μg/mL of BIRB796 at each concentration of test compound by comparisonagainst vehicle control. The relative 50% effective concentration(REC₅₀) is determined from the resultant concentration-response curve.The inhibition of IL-8 production is calculated at each concentration oftest compound by comparison with vehicle control. The 50% inhibitoryconcentration (IC₅₀) is determined from the resultantconcentration-response curve.

(b) LPS-Induced TNFα/IL-8 Release in PBMC Cells

Peripheral blood mononuclear cells (PBMCs) from healthy subjects areseparated from whole blood using a density gradient (Lymphoprep,Axis-Shield Healthcare). The PBMCs are seeded in 96 well plates andtreated with compounds at the desired concentration for 2 hours beforeaddition of 1 ng/mL LPS (Escherichia Coli 0111:B4 from Sigma Aldrich)for 24 hours under normal tissue culture conditions (37° C., 5% CO₂).The supernatant is harvested for determination of IL-8 and TNFαconcentrations by sandwich ELISA (Duo-set, R&D systems) and read on thefluorescence microplate reader (Varioskan® Flash, ThermoFisherScientific). The concentration at 50% inhibition (IC₅₀) of IL-8 and TNFαproduction is calculated from the dose response curve.

(c) IL-2 and IFN Gamma Release in CD3/CD28 Stimulated PBMC Cells

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells are addedto a 96 well plate pre-coated with a mixture of CD3/CD28 monoclonalantibodies (0.3 μg/mL eBioscience and 3 μg/mL BD Pharmingenrespectively). Compound at the desired concentration is then added tothe wells and the plate left for 3 days under normal tissue cultureconditions. Supernatants are harvested and IL-2 and IFN gamma releasedetermined by Sandwich ELISA (Duo-set, R&D System). The IC₅₀ isdetermined from the dose response curve.

(d) IL-1β-Induced IL-8 Release in HT29 Cells

HT29 cells, a human colon adenocarcinoma cell line, are plated in a 96well plate (24 hr) and pre-treated with compounds at the desiredconcentration for 2 hours before addition of 5 ng/mL of IL-1β (Abcam)for 24 hours. Supernatants are harvested for IL-8 quantification bySandwich ELISA (Duo-set, R&D System). The IC₅₀ is determined from thedose response curve.

(e) LPS-Induced IL-8 and TNFα Release in Primary Macrophages

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells areincubated for 2 hrs and non-adherent cells removed by washing. Todifferentiate the cells to macrophages, they are incubated with 5 ng/mLof GM-CSF (Peprotech) for 7 days under normal tissue culture conditions.Compounds are then added to the cells at the desired concentration for a2 hour pre-treatment before stimulation with 10 ng/mL LPS for 24 hours.Supernatants are harvested and IL-8 and TNFα release determined bySandwich ELISA (Duo-set, R&D System). The IC₅₀ is determined from thedose response curve.

(f) Poly I:C-Induced ICAM-1 Expression in BEAS2B Cells

Poly I:C is used in these studies as a simple, RNA virus mimic. PolyI:C-Oligofectamine mixture (1 μg/mL Poly I:C, ±2% Oligofectamine, 25 μL;Invivogen Ltd., San Diego, Calif., and Invitrogen, Carlsbad, Calif.,respectively) is transfected into BEAS2B cells (human bronchialepithelial cells, ATCC). Cells are pre-incubated with finalconcentrations of test compounds for 2 hr and the level of ICAM1expression on the cell surface is determined by cell-based ELISA. At atime point 18 hr after poly I:C transfection, cells are fixed with 4%formaldehyde in PBS and then endogenous peroxidase is quenched by theaddition of washing buffer (100 μL, 0.05% Tween in PBS: PBS-Tween)containing 0.1% sodium azide and 1% hydrogen peroxide. Cells are washedwith wash-buffer (3×200 μL) and after blocking the wells with 5% milk inPBS-Tween (100 μL) for 1 hr, the cells are incubated with anti-humanICAM-1 antibody (50 μL; Cell Signalling Technology, Danvers, Mass.) in1% BSA PBS overnight at 4° C.

The cells are washed with PBS-Tween (3×200 μL) and incubated with thesecondary antibody (100 μL; HRP-conjugated anti-rabbit IgG, Dako Ltd.,Glostrup, Denmark). The cells are then incubated with substrate (50 μL)for 2-20 min, followed by the addition of stop solution (50 μL, 1NH₂SO₄). The ICAM-1 signal is detected by reading the absorbance at 450nm against a reference wavelength of 655 nm using a spectrophotometer.The cells are then washed with PBS-Tween (3×200 μL) and total cellnumbers in each well are determined by reading absorbance at 595 nmafter Crystal Violet staining (50 μL of a 2% solution in PBS) andelution by 1% SDS solution (100 μL) in distilled water. The measured OD450-655 readings are corrected for cell number by dividing with theOD595 reading in each well. The inhibition of ICAM-1 expression iscalculated at each concentration of test compound by comparison withvehicle control. The 50% inhibitory concentration (IC₅₀) is determinedfrom the resultant concentration-response curve.

(g) Cell Mitosis Assay

Peripheral blood mononucleocytes (PBMCs) from healthy subjects areseparated from whole blood (Quintiles, London, UK) using a densitygradient (Histopaque®-1077, Sigma-Aldrich, Poole, UK). The PBMCs (3million cells per sample) are subsequently treated with 20% PHA(phytohaemagglutinin, Sigma-Aldrich, Poole, UK) for 48 hr, followed by a20 hr exposure to varying concentrations of test compounds. At 2 hrbefore collection, PBMCs are treated with demecolcine (0.1 μg/mL;Invitrogen, Paisley, UK) to arrest cells in metaphase. To observemitotic cells, PBMCs are permeabilised and fixed by adding Intraprep (50μL; Beckman Coulter, France), and stained with anti-phospho-histone 3(0.26 ng/L; #9701; Cell Signalling, Danvers, Mass.) and propidium iodide(1 mg/mL; Sigma-Aldrich, Poole, UK) as previously described (MuehlbauerP. A. and Schuler M. J., Mutation Research, 2003, 537:117-130).Fluorescence is observed using an ATTUNE flow cytometer (Invitrogen,Paisley, UK), gating for lymphocytes. The percentage inhibition ofmitosis is calculated for each treatment relative to vehicle (0.5% DMSO)treatment.

(h) Rhinovirus-Induced IL-8 Release and ICAM-1 Expression

Human rhinovirus RV16 is obtained from the American Type CultureCollection (Manassas, Va.). Viral stocks are generated by infecting HeLacells with HRV until 80% of the cells are cytopathic.

BEAS2B cells are infected with HRV at an MOI of 5 and incubated for 2 hrat 33° C. with gentle shaking to promote absorption. The cells are thenwashed with PBS, fresh media added and the cells are incubated for afurther 72 hr. The supernatant is collected for assay of IL-8concentrations using a Duoset ELISA development kit (R&D systems,Minneapolis, Minn.).

The level of ICAM-1 expressing cell surface is determined by cell-basedELISA. At 72 hr after infection, cells are fixed with 4% formaldehyde inPBS. After quenching endogenous peroxidase by adding 0.1% sodium azideand 1% hydrogen peroxide, wells are washed with wash-buffer (0.05% Tweenin PBS: PBS-Tween). After blocking well with 5% milk in PBS-Tween for 1hr, the cells are incubated with anti-human ICAM-1 antibody in 5% BSAPBS-Tween (1:500) overnight. Wells are washed with PBS-Tween andincubated with the secondary antibody (HRP-conjugated anti-rabbit IgG,Dako Ltd.). The ICAM-1 signal is detected by adding substrate andreading at 450 nm with a reference wavelength of 655 nm using aspectrophotometer. The wells are then washed with PBS-Tween and totalcell numbers in each well are determined by reading absorbance at 595 nmafter Crystal Violet staining and elution with 1% SDS solution. Themeasured OD₄₅₀₋₈₅₅ readings are corrected for cell number by dividingwith the OD₅₉₅ reading in each well. Compounds are added 2 hr before HRVinfection and 2 hr after infection when non-infected HRV is washed out.

(i) Assessment of HRV16 Induced Cytopathic Effect (CPE) in MRC5 Cells

MRC5 cells are infected with HRV16 at an MOI of 1 in DMEM containing 5%FCS and 1.5 mM MgCl₂, followed by incubation for 1 hr at 33° C. topromote adsorption. The supernatants are aspirated, and then fresh mediaadded followed by incubation for 4 days. Where appropriate, cells arepre-incubated with compound or DMSO for 2 hr, and the compounds and DMSOadded again after washout of the virus.

Supernatants are aspirated and incubated with methylene blue solution(100 μL, 2% formaldehyde, 10% methanol and 0.175% Methylene Blue) for 2hr at RT. After washing, 1% SDS in distilled water (100 μL) is added toeach well, and the plates are shaken lightly for 1-2 hr prior to readingthe absorbance at 660 nm. The percentage inhibition for each well iscalculated. The IC₅₀ value is calculated from the concentration-responsecurve generated by the serial dilutions of the test compounds.

(j) In Vitro RSV Virus Load in Primary Bronchial Epithelial Cells

Normal human bronchial epithelial cells (NHBEC) grown in 96 well platesare infected with RSV A2 (Strain A2, HPA, Salisbury, UK) at a MOI of0.001 in the LHC8 Media:RPMI-1640 (50:50) containing 15 mM magnesiumchloride and incubated for 1 hr at 37° C. for adsorption. The cells arewashed with PBS (3×200 μL), then fresh media (200 μL) is added andincubation continued for 4 days. Where appropriate, cells arepre-incubated with the compound or DMSO for 2 hr, and then added againafter washout of the virus.

The cells are fixed with 4% formaldehyde in PBS solution (50 μL) for 20min, washed with WB (3×200 μL) (washing buffer, PBS including 0.5% BSAand 0.05% Tween-20) and incubated with blocking solution (5% condensedmilk in PBS) for 1 hr. Cells are then washed with WB (3×200 μL) andincubated for 1 hr at RT with anti-RSV (2F7) F-fusion protein antibody(40 μL; mouse monoclonal, lot 798760, Cat. No. ab43812, Abcam) in 5% BSAin PBS-tween. After washing, cells are incubated with an HRP-conjugatedsecondary antibody solution (50 μL) in 5% BSA in PBS-Tween (lot00053170, Cat. No. P0447, Dako) and then TMB substrate added (50 μL;substrate reagent pack, lot 269472, Cat. No. DY999, R&D Systems, Inc.).This reaction is stopped by the addition of 2N H₂SO₄ (50 μL) and theresultant signal is determined colourimetrically (OD: 450 nm with areference wavelength of 655 nm) in a microplate reader (Varioskan®Flash, ThermoFisher Scientific).

Cells are then washed and a 2.5% crystal violet solution (50 μL; lot8656, Cat. No. PL7000, Pro-Lab Diagnostics) is applied for 30 min. Afterwashing with WB, 1% SDS in distilled water (100 μL) is added to eachwell, and plates are shaken lightly on the shaker for 1 hr prior toreading the absorbance at 595 nm. The measured OD₄₅₀₋₈₅₅ readings arecorrected to the cell number by dividing the OD₄₅₀₋₈₅₅ by the OD₅₉₅readings. The percentage inhibition for each well is calculated and theIC₅₀ value is calculated from the concentration-response curve generatedfrom the serial dilutions of compound.

(k) Cell Viability Assay: MTT Assay

Differentiated U937 cells are pre-incubated with each test compound(final concentration 1 μg/mL or 10 μg/mL in 200 μL media indicatedbelow) under two protocols: the first for 4 hr in 5% FCS RPMI1640 mediaand the second in 10% FCS RPMI1640 media for 24 h. The supernatant isreplaced with new media (200 μL) and MTT stock solution (10 μL, 5 mg/mL)is added to each well. After incubation for 1 hr the media are removed,DMSO (200 μL) is added to each well and the plates are shaken lightlyfor 1 hr prior to reading the absorbance at 550 nm. The percentage lossof cell viability is calculated for each well relative to vehicle (0.5%DMSO) treatment. Consequently an apparent increase in cell viability fordrug treatment relative to vehicle is tabulated as a negativepercentage.

(l) Human Biopsy Assay

Intestinal mucosa biopsies are obtained from the inflamed regions of thecolons of IBD patients. The biopsy material is cut into small pieces(2-3 mm) and placed on steel grids in an organ culture chamber at 37° C.in a 5% CO₂/95% O₂ atmosphere in serum-free media. DMSO control or testcompounds at the desired concentration are added to the tissue andincubated for 24 hr in the organ culture chamber. The supernatant isharvested for determination of IL-6, IL-8, IL-1β and TNFα levels by R&DELISA. Percentage inhibition of cytokine release by the test compoundsis calculated relative to the cytokine release determined for the DMSOcontrol (100%).

(m) Accumulation of β Catenin in d-U937 Cells

U937 cells, a human monocytic cell line, are differentiated intomacrophage-type cells by incubation with PMA (100 ng/mL) for between 48to 72 hr. The cells are then incubated with either final concentrationsof test compound or vehicle for 18 hr. The induction of β-catenin by thetest compounds is stopped by replacing the media with 4% formaldehydesolution. Endogenous peroxide activity is neutralised by incubating withquenching buffer (100 μL, 0.1% sodium azide, 1% H₂O₂ in PBS with 0.05%Tween-20) for 20 min. The cells are washed with washing buffer (200 μL;PBS containing 0.05% Tween-20) and incubated with blocking solution (200μL; 5% milk in PBS) for 1 hr, re-washed with washing buffer (200 μL) andthen incubated overnight with anti-β-catenin antibody solution (50 μL)in 1% BSA/PBS (BD, Oxford, UK).

After washing with washing buffer (3×200 μL; PBS containing 0.05%Tween-20), cells are incubated with a HRP-conjugated secondary antibodysolution (100 μL) in 1% BSA/PBS (Dako, Cambridge, UK) and the resultantsignal is determined colourimetrically (OD: 450 nm with a referencewavelength of 655 nm) using TMB substrate (50 μL; R&D Systems, Abingdon,UK). This reaction is stopped by addition of 1N H₂SO₄ solution (50 μL).Cells are then washed with washing buffer and 2% crystal violet solution(50 μL) is applied for 30 min. After washing with washing buffer (3×200μL), 1% SDS (100 μL) is added to each well and the plates are shakenlightly for 1 hr prior to measuring the absorbance at 595 nm (Varioskan®Flash, Thermo-Fisher Scientific).

The measured OD₄₅₀₋₈₅₅ readings are corrected for cell number bydividing the OD₄₅₀₋₈₅₅ by the OD₅₉₅ readings. The percentage inductionfor each well is calculated relative to vehicle, and the ratio ofinduction normalised in comparison with the induction produced by astandard control comprising the Reference compoundN-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide(1 μg/mL), which is defined as unity.

(n) T Cell Proliferation

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). The lymphocytefraction is first enriched for CD4+ T cells by negative magnetic cellsorting as per the manufacturer's instructions (Miltenyi Biotec130-091-155). Naïve CD4+ T cells are then separated using positivemagnetic selection of CD45RA+ cells using microbeads as per themanufacturer's instructions (130-045-901). Cells are plated at 2×10⁵cells per well in 100 μL RPMI/10% FBS on 96 well flat bottomed plate(Corning Costar). 25 μL of test compound are diluted to the appropriateconcentration (8× final concentration) in normal medium and added toduplicate wells on the plate to achieve a dose response range of 0.03ng/mL-250 ng/mL. DMSO is added as a negative control. Plates are allowedto pre-incubate for 2 hours before stimulation with 1 μg/mL anti-CD3(OKT3; eBioscience). After 72 h, the medium in each well is replacedwith 150 μL of fresh medium containing 10 μM BrdU (Roche). After 16 h,the supernatant is removed, the plate is dried and the cells fixed byadding 100 μL of fix/denature solution to each well for 20 min as perthe manufacturer's instructions (Roche). Plates are washed once with PBSbefore addition of the anti-BrdU detection antibody and incubated for 90mins at room temperature. Plates are then washed gently 3× with the washbuffer supplied and developed by addition of 100 μL of substratesolution. The reaction is stopped by addition of 50 μL of 1 M H₂SO₄ andread for absorbance at 450 nm on a plate reader (Varioskan® Flash,ThermoFisher Scientific). The IC₅₀ is determined from the dose responsecurve.

(o) IL-2 and IFNγ Release in CD3/CD28 Stimulated LPMC Cells from IBDPatients

Lamina propria mononuclear cells (LPMCs) are isolated and purified frominflamed IBD mucosa of surgical specimens or from normal mucosa ofsurgical specimens as follows:

The mucosa is removed from the deeper layers of the surgical specimenswith a scalpel and cut in fragments of size 3-4 mm. The epithelium isremoved by washing the tissue fragments three times with 1 mM EDTA(Sigma-Aldrich, Poole, UK) in HBSS (Sigma-Aldrich) with agitation usinga magnetic stirrer, discarding the supernatant after each wash. Thesample is subsequently treated with type 1A collagenase (1 mg/mL;Sigma-Aldrich) for 1 h with stirring at 37° C. The resulting cellsuspension is then filtered using a 100 μm cell strainer, washed twice,resuspended in RPMI-1640 medium (Sigma-Aldrich) containing 10% fetalcalf serum, 100 U/mL penicillin and 100 μg/mL streptomycin, and used forcell culture.

Freshly isolated LPMCs (2×10⁵ cells/well) are stimulated with 1 μg/mLα-CD3/α-CD28 for 48 h in the presence of either DMSO control orappropriate concentrations of compound. After 48 h, the supernatant isremoved and assayed for the presence of TNFα and IFNγ by R&D ELISA.Percentage inhibition of cytokine release by the test compounds iscalculated relative to the cytokine release determined for the DMSOcontrol (100%).

(p) Inhibition of Cytokine Release from Myofibroblasts Isolated from IBDPatients

Myofibroblasts from inflamed IBD mucosa are isolated as follows:

The mucosa is dissected and discarded and 1 mm-sized mucosal samples arecultured at 37° C. in a humidified CO₂ incubator in Dulbecco's modifiedEagle's medium (DMEM, Sigma-Aldrich) supplemented with 20% FBS, 1%non-essential amino acids (Invitrogen, Paisley, UK), 100 U/mLpenicillin, 100 μg/mL streptomycin, 50 μg/mL gentamycin, and 1 μg/mLamphotericin (Sigma-Aldrich). Established colonies of myofibroblasts areseeded into 25-cm² culture flasks and cultured in DMEM supplemented with20% FBS and antibiotics to at least passage 4 to provide a sufficientquantity for use in stimulation experiments.

Subconfluent monolayers of myofibroblasts, seeded in 12-well plates at3×10⁵ cells per well, are starved in serum-free medium for 24 h at 37°C., 5% CO₂, before being cultured for 24 h in the presence of eitherDMSO control or appropriate concentrations of compound. After 24 h, thesupernatant is removed and assayed for the presence of IL-8 and IL-6 byR&D ELISA. Percentage inhibition of cytokine release by the testcompounds is calculated relative to the cytokine release determined forthe DMSO control (100%).

(q) Human Neutrophil Degranulation

Neutrophils are isolated from human peripheral blood as follows:

Blood is collected by venepuncture and anti-coagulated by addition of1:1 EDTA:sterile phosphate buffered saline (PBS, no Ca+/Mg+). Dextran(3% w/v) is added (1 part dextran solution to 4 parts blood) and theblood allowed to stand for approximately 20 minutes at rt. Thesupernatant is carefully layered on a density gradient (Lymphoprep,Axis-Shield Healthcare) and centrifuged (15 mins, 2000 rpm, no brake).The supernatant is aspirated off and the cell pellet is re-suspended insterile saline (0.2%) for no longer than 60 seconds (to lysecontaminating red blood cells). 10 times volume of PBS is then added andthe cells centrifuged (5 mins, 1200 rpm). Cells are re-suspended inHBSS+ (Hanks buffered salt solution (without phenol red) containingcytochalasin B (5 μg/mL) and 1 mM CaCl₂) to achieve 5×10⁶ cells/mL.

5×10⁴ cells are added to each well of a V-bottom 96 well plate and areincubated (30 mins, 37° C.) with the appropriate concentration of testcompound (0.3-1000 ng/mL) or vehicle (DMSO, 0.5% final conc).Degranulation is stimulated by addition of fMLP (final concentration 1μM). After a further incubation (30 mins, 37° C.), the cells are removedby centrifugation (5 mins, 1500 rpm) and the supernatants transferred toa flat bottom 96 well plate. An equal volume of tetramethylbenzidine(TMB) is added and, after 10 mins, the reaction terminated by additionof an equal volume of sulphuric acid (0.5 M) and absorbance read at 450nm (background at 655 nm subtracted). The 50% inhibitory concentration(IC₅₀) is determined from the resultant concentration-response curve.

(r) Cell Cytotoxicity Assay

1×10⁵ Jurkat cells (immortalised human T lymphocytes) are added to theappropriate number of wells of a 96 well plate in 100 μL of media (RPMIsupplemented with 10% foetal bovine serum). 1 μL of DMSO control (finalconcentration 1.0% v/v) or test compound (final concentration 20, 5 or 1μg/mL) is added to the wells and incubated at 37° C., 5% CO₂. After 24hours, the plate is centrifuged at 1200 rpm for 3 minutes and thesupernatant discarded. Cells are then resuspended in 150 μL (finalconcentration 7.5 μg/mL) of propidium iodide (PI) in PBS and incubatedat 37° C., 5% CO₂ for 15 minutes. After 15 minutes, cells are analysedby flow cytometry (BD accuri) using the FL3 window. The % viability iscalculated as the % of cells that are P negative in the test wellsnormalised to the DMSO control.

In Vivo Screening: Pharmacodynamics and Anti-Inflammatory Activity

(i) LPS-induced Neutrophil Accumulation in Mice

Non-fasted Balb/c mice are dosed by the intra tracheal route with eithervehicle, or the test substance at the indicated times (within the range2-8 hr) before stimulation of the inflammatory response by applicationof an LPS challenge. At T=0, mice are placed into an exposure chamberand exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBS) for 30 min. Aftera further 8 hr, the animals are anesthetized, their tracheas cannulatedand BALF extracted by infusing and then withdrawing from their lungs 1.0mL of PBS via the tracheal catheter. Total and differential white cellcounts in the BALF samples are measured using a Neubauer haemocytometer.Cytospin smears of the BALF samples are prepared by centrifugation at200 rpm for 5 min at RT and stained using a DiffQuik stain system (DadeBehring). Cells are counted using oil immersion microscopy. Data forneutrophil numbers in BAL are represented as mean±S.E.M. (standard errorof the mean). The percentage inhibition of neutrophil accumulation iscalculated for each treatment relative to vehicle treatment.

(ii) Cigarette Smoke Model

A/J mice (males, 5 weeks old) are exposed to cigarette smoke (4%cigarette smoke, diluted with air) for 30 min/day for 11 days using aTobacco Smoke Inhalation Experiment System for small animals (ModelSIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test substances areadministered intra-nasally (35 μL of solution in 50% DMSO/PBS) oncedaily for 3 days after the final cigarette smoke exposure. At 12 hrafter the last dosing, each of the animals is anesthetized, the tracheacannulated and bronchoalveolar lavage fluid (BALF) is collected. Thenumbers of alveolar macrophages and neutrophils are determined by FACSanalysis (EPICS® ALTRA II, Beckman Coulter, Inc., Fullerton, Calif.,USA) using anti-mouse MOMA2 antibody (macrophage) or anti-mouse 7/4antibody (neutrophil).

(iii) DSS-induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle, reference item (5-ASA) or test compoundone day before (Day −1) stimulation of the inflammatory response bytreatment with dextran sodium sulphate (DSS). On Day 0 of the study, DSS(5% w/v) is administered in the drinking water followed by BID dosing ofthe vehicle (5 mL/kg), reference (100 mg/kg) or test compound (5 mg/kg)for 7 days. The drinking water with DSS is replenished every 3 days.During the study, animals are weighed every day and stool observationsare made and recorded as a score, based on stool consistency. At thetime of sacrifice on Day +6, the large intestine is removed and thelength and weight are recorded. Sections of the colon are taken foreither MPO analysis, to determine neutrophil infiltration, or forhistopathology scoring to determine disease severity.

(iv) TNBS-induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle (5 mL/kg), reference item (Budesonide2.5 mg/kg) or test compound (1 or 5 mg/kg) one day before (Day −1)stimulation of the inflammatory response by treatment with2,4,6-trinitrobenzenesulphonic acid (TNBS) (15 mg/mL in 50% ethanol/50%saline). On Day 0 of the study TNBS (200 μL) is administeredintra-colonically via a plastic catheter with BID dosing of the vehicle,reference or test compound continuing for 2 or 4 days. During the study,animals are weighed every day and stool observations are made andrecorded as a score, based on stool consistency. At the time ofsacrifice on Day 2 (or Day 4), the large intestine is removed and thelength and weight recorded. Sections of the colon are taken forhistopathology scoring to determine disease severity.

(v) Adoptive Transfer in Mice

On Study day 0, female Balb/C mice are terminated and spleens obtainedfor CD45RB^(high) cell isolation (Using SCID IBD cell Separationprotocol). Approximately 4×10⁵ cells/mL CD45RB^(high) cells are theninjected intraperitoneally (100 μL/mouse) into female SCID animals. Onstudy day 14, mice are weighed and random/zed into treatment groupsbased on body weight. On Day 14, compounds are administered BID, viaoral gavage, in 5% polyoxyethylene 40 stearate in 20 mM pH 7.8 aqueousphosphate buffer in a dose volume of 5 mL/kg. Treatment continues untilstudy day 49, at which point the animals are necropsied 4 hours afterthe morning administration. The colon length and weight are recorded andused as a secondary endpoint in the study as a measurement of colonoedema. The colon is then divided into six cross-sections, four of whichare used for histopathology scoring (primary endpoint) and two arehomogenised for cytokine analysis. Data shown is the % inhibition of theinduction window between naïve animals and vehicle animals, where higherinhibition implies closer to the non-diseased, naïve, phenotype.

(vi) Endotoxin-induced Uveitis in Rats

Male, Lewis rats (6-8 weeks old, Charles River UK Limited) are housed incages of 3 at 19-21° C. with a 12 h light/dark cycle (07:00/19:00) andfed a standard diet of rodent chow and water ad libitum. Non-fasted ratsare weighed, individually identified on the tail with a permanentmarker, and receive a single intravitreal administration into the rightvitreous humor (5 μL dose volume) of 100 ng/animal of LPS (Escherichiacoli 0111:B4 prepared in PBS, Sigma Aldrich, UK) using a 32-gaugeneedle. Untreated rats are injected with PBS. Test compound or vehicle(4% polyoxyl 40 stearate, 4% mannitol in PBS (pH 7.4)) are administeredby the topical route onto the right eye (10 μL) of animals 1 hour priorto LPS, at the time of LPS administration, and 1, 2 and 4 hours post LPSadministration. Before administration, the solution to be administeredis sonicated to ensure a clear solution. 6 hours after LPS dosing,animals are euthanized by overdose with pentobarbitone (via cardiacpuncture). Immediately after euthanasia, 10 μL of aqueous humor iscollected from the right eye of the rats by puncture of the anteriorchamber using a 32 gauge needle under a surgical microscope. The aqueoushumor is diluted in 20 μL of PBS and total cell counts are measuredimmediately using a Countess automated cell counter (Invitrogen).Following collection of the aqueous humour, the right eye of each animalis enucleated and dissected into front (anterior) and back (posterior)sections around the lens. Each section is weighed and homogenised in 500μL of sterile phosphate buffered saline followed by 20 minutescentrifugation at 12000 rpm at 4° C. The resulting supernatant isdivided into 3 aliquots and stored at −80° C. until subsequent cytokineanalysis by R&D DuoSet ELISA.

Summary of In Vitro and In Vivo Screening Results

TABLE 1 Results from in vitro p38 MAPKα (Method 2), c-Src and Sykinhibition assays Test Compound IC50 Values for Enzyme Inhibition (nM)Example No. p38 MAPKα c-Src Syk 1 — — — 2 23 14 8 3 23 18 12

TABLE 2 Inhibition of cytokine release in stimulated cells (assays (b)and (c) above). Test Compound IC50 Values in PBMCs (nM) Example No. IL-8IFNγ TNFα  1 115.1 — —  2 24.6 39.4 —  3 17.3 31.8 10.8  5 19.5 — —  618.1 — —  7 20.8 — —  8 8.0 — —  9 11.7 — — 10 26.5 — — 11 11.7 — — 125.6 — — 13 2.8 — — 14 7.3 — — 15 16.4 — — 16 16.3 — — 17 17.2 — — 1829.3 — — 19 2.9 — —   20(a) 10.4 — —   20(b) 19.1 — — 21 14.4 — — 2218.1 — — 23 29.2 — — 24 61.9 — — 25 26.3 — — 26 15.3 — — 27 7.3 — — 2820.6 — —

As illustrated in Table 3 below, compounds of the examples of thepresent invention are substantially less cytotoxic than the ReferenceCompound (N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl) ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide; WO 2010/112936),displaying enhanced viabilities in cell cytotoxicity assay (r) above(Table 3). In addition, the compounds of the examples of the presentinvention are substantially less cytotoxic at 20 μg/mL than theReference Compound A(3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid; WO 2014162126).

TABLE 3 Effect of compounds of the examples on Jurkat cell viability(assay (r) above; NT = not tested). Test % Viability % Viability %Viability compound at 1 μg/mL at 5 μg/mL at 20 μg/mL Reference 29 26 24compound Reference 96 93 48 compound A 1 NT NT NT 2 99 99 97 3 99 99 96

As illustrated in Table 4 below, the compound of Example 3 was alsoscreened in the in vivo (adoptive transfer) assay (v) above alongsideReference Compound A,(3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid, and Reference Compound B,3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide{Fyfe, M. C. T., WO 2014/140582}. Analysis of the relative ratios ofcolon weight to length in naïve, control and treated animals at the endof the study revealed that the compound of Example 3 provided superioractivity compared to the two Reference Compounds in this T cell drivenin vivo model of colonic inflammation using a simple aqueous-basedvehicle.

TABLE 4 Summary of results from adoptive transfer mouse model. Treatmentgroup Dose Colon weight:length % Inhibition Naïve N/A 0.021 ± 0.001 100Vehicle control N/A 0.043 ± 0.007 0 Reference Compound A 3 mg/kg^([†])0.047 ± 0.007 −14 Reference Compound B 3 mg/kg 0.041 ± 0.005 11 Example3 3 mg/kg 0.032 ± 0.004 49 ^([†])Dose was lowered to 0.6 mg/kg on day 27because of poor tolerability (body weight loss).Summary of Additional StudiesDetermination of Solubilities in Fasted-State Simulated Colonic Fluid(FaSSCoF)

The solubilities of compounds of the invention in FaSSCoF at pH 6.5 aredetermined using a modification of a previously-reported procedure(Vertzoni, M., et al. Pharm. Res. 2010, 27, 2187-2196). In place of thebile salt extract employed in the original procedure (which extract isno longer available), the modified procedure uses a mixture of sodiumtaurocholate (0.15 g), glycocholic acid (0.15 g), ursodeoxycholic acid(0.05 g), cholic acid (0.05 g), and glycodeoxycholic acid (0.05 g).These five bile acids are ground together with a mortar and pestle toproduce a fine white powder that is incorporated into the FaSSCoF, asoutlined below.

FaSSCoF medium: Tris(hydroxymethyl)aminomethane (Tris; 0.275 g) andmaleic acid (0.44 g) are dissolved in water (35 mL) to give a solutionwhose pH is adjusted to 6.5 by treatment with 0.5M NaOH (ca. 12 mL). Thesolution is then made up to 50 mL with water. A portion of thisTris/maleate buffer solution (ca. 25 mL) is added to a 0.5 Lround-bottomed flask, before being treated with 0.00565 g of the bileacid mixture described above. Solutions of phosphatidylcholine (0.0111g) in DCM (0.15 mL) and palmitic acid (0.0013 g) in DCM (0.15 mL) areadded, then the organic solvent is evaporated off under reduced pressureat 40° C. until a clear solution, with no perceptible DCM odour, isachieved. The volume of the evaporated solution is adjusted to 50 mL byaddition of the remainder of Tris/maleate buffer, then BSA (0.115 g) isadded, before being dissolved by gentle agitation.

Solubility Determination: Test compounds are suspended in the pH 6.5FaSSCoF medium to give a maximum final concentration of 2-10 mg/mL. Thesuspensions are equilibrated at 25° C. for 24 h, before being filteredthrough a glass fibre C filter. The filtrates are then diluted asappropriate for injection and quantification by HPLC with reference to astandard. Different volumes of the standard, diluted and undilutedsample solutions are injected and the solubilities are calculated usingthe peak areas determined by integration of the peak found at the sameretention time as the principal peak in the standard injection.

FaSSCoF solubilities are shown in Table 5 below, which reveals thatcompounds of the Examples (or salts thereof) exhibited solubilities inthe FaSSCoF medium at pH 6.5 in excess of 0.03 mg/mL, while somedisplayed solubilities greater than 1 mg/mL. The pH 6.5 FaSSCoFsolubilities measured for compounds of the Examples were superior tothose of both Reference Compound A,(3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methyl-sulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)-ethoxy)ethoxy)propanoicacid, and Reference Compound B,3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide{Fyfe, M. C. T., WO 2014/140582}.

TABLE 5 Solubilities measured for certain compounds of the Examples ofthe present invention, or salts thereof, in FaSSCoF at pH 6.5. TestCompound pH 6.5 FaSSCoF Solubility (mg/mL) Example No. Run 1 Run 2 Run 3Run 4 Reference Compound A 0.007 0.007 — — Reference Compound A 0.180.12 0.03 0.03 (sodium salt) Reference Compound B <0.001 <0.001 — —  20.09 0.06 — — 2 (sodium salt) 0.58 — — —  3 0.28 0.20 — — 31 1.90 2.10 ——  8 2.8 3.2 — —  9 0.46 0.54 — — 14 1.2 1.1 — — 17 1.7 1.5 — — 19 0.030.03 — —   20(a) 0.62 0.64 — —

Further studies also revealed that, in phosphate-buffered saline ateither pH 6.5 with 0.5% by weight of simulated intestinal fluid or pH7.2, the compound of Example 31 (i.e. the sodium of the compound ofExample 3) was both more soluble than, and had a faster dissolution ratethan, both of Reference Compounds A (hydrochloride salt) and B.

Microcentrifuge Dissolution Tests

In vitro non-sink dissolution performance of the Compound of Example 3was evaluated alongside Reference Compounds A and B employingmicrocentrifuge dissolution tests in which samples were either 1)transferred from intestinal buffer (IB) to colonic buffer (CB) or 2)dosed directly into intestinal media containing simulated bile-saltmicelles (IB-SIF). Dissolution performance of the compounds at varioustimepoints was determined by centrifugation and analysis of thesupernatant concentrations by off-line reverse-phase HPLC analysis.

1) Transfer from Intestinal Buffer (IB) to Colonic Buffer (CB)Experiment

Test compounds (0.45 mg±0.05 mg) were weighed into a microcentrifugetube, then 0.900 mL of IB receptor solution—phosphate buffered saline(PBS) warmed to 37° C. at pH 6.5—was added. A timer was started and thesample tubes were vortexed at the maximum setting for 1 minute. When thetimer read 3, 13 and 23 min—corresponding to the 25, 15 and 5 mintimepoints, respectively—the sample tubes were centrifuged for 1 min at15,800 Relative Centrifugal Force (RCF). At each timepoint, a portion ofthe supernatant (50 μL) was added to diluent {250 μL of 75/25 THF/Water(v/v)} and the compound concentrations were measured by off-line HPLCanalysis (Table 6a). After a further 5 min, 0.900 mL of CB receptorsolution—pH 10.7 PBS solution—was added, such that the pH was adjustedto 7.2, and the timer was reset to 0 min. When the timer read 2, 8, 18,38, 88 and 1,198 min—corresponding to the 4, 10, 20, 40, 90 and 1,200min timepoints, respectively—the sample tubes were centrifuged for 1 minat 15,800 RCF. At each timepoint, a portion of the supernatant (50 μL)was added to diluent {250 μL of 75/25 THF/Water (v/v)} and the compoundconcentrations were measured by off-line HPLC analysis (Table 6a). TheHPLC samples for the 90 and 1,200 min timepoints were additionallycentrifuged for 8 min at 80,000 rpm at 37° C. in an ultracentrifuge(UCF), then the supernatant (50 μL) was added to diluent {250 μL of75/25 THF/Water (v/v)} and the compound concentrations were measured byoff-line HPLC analysis (Table 6b) to determine the concentration of freedrug+drug in micelles.

TABLE 6a Concentrations (μg/mL) measured during dissolution test 1).Test Cpd IB Timepoint (min) CB Timepoint (min) Example No. −30 −25 −15−5 4 10 20 40 90 1,200 Reference 0.0 2.9 4.6 5.3 11.4 11.5 10.7 10.7 8.47.9 Compound A Reference 0.0 1.9 1.0 2.2 5.0 1.9 0.9 0.6 0.0 4.9Compound B 3 0.0 5.3 7.5 8.5 9.3 9.1 14.3 48.3 60.7 85.4

TABLE 6b Additional concentrations (μg/mL) measured during dissolutiontest 1). UCF Timepoint (min) Test Compound Example No. 90 1,200Reference Compound A 5.1 3.9 Reference Compound B 0.0 1.6 3 34.1 74.92) Experiment with Direct Dosing into Intestinal Media ContainingSimulated Bile-salt Micelles (IB-SIF)

Test compounds (0.45 mg±0.05 mg) were weighed into a microcentrifugetube then 1.800 mL of IB-SIF receptor solution—prepared previously bydissolution of 0.250 g SIF powder (Biorelevant.com) in 50 mL of pH 6.5PBS warmed to 37° C.—was added. A timer was started and the sample tubeswere vortexed at the maximum setting for 1 minute. When the timer read2, 8, 18, 38, 88 and 1,198 min—corresponding to the 4, 10, 20, 40, 90and 1,200 min timepoints, respectively—the sample tubes were centrifugedfor 1 min at 15,800 RCF. Then, at each timepoint, the supernatant (50μL) was added to diluent {250 μL of 75/25 THF/Water (v/v)} and thecompound concentrations were measured by off-line HPLC analysis (Table7a). To determine the concentration of free drug+drug in micelles, theHPLC samples for the 90 and 1,200 min timepoints were additionallycentrifuged for 8 min at 80,000 rpm at 37° C. in an ultracentrifuge(UCF), then the supernatant (50 μL) was added to diluent {250 PL of75/25 THF/Water (v/v)} and the compound concentrations were measured byoff-line HPLC analysis (Table 7b).

TABLE 7a Concentrations (μg/mL) measured during dissolution test 2).Test Compound IB Timepoint (min) Example No. 0 4 10 20 40 90 1,200Reference 0.0 39.8 63.4 83.5 96.5 99.9 101.0 Compound A Reference 0.01.1 0.9 1.3 1.0 0.7 3.0 Compound B 3 0.0 255.7 255.9 251.7 249.2 253.5239.0

TABLE 7b Additional concentrations (μg/mL) measured during dissolutiontest 2). UCF Timepoint (min) Test Compound Example No. 90 1,200Reference Compound A 87.0 88.8 Reference Compound B 0.7 2.9 3 229.4169.9Abbreviations

-   -   AcOH glacial acetic acid    -   aq aqueous    -   5-ASA 5-aminosalicylic acid    -   ATP adenosine-5′-triphosphate    -   BALF bronchoalveolar lavage fluid    -   BID bis in die (twice-daily)    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexafluorophosphate    -   br broad    -   BrdU 5-bromo-2′-deoxyuridine    -   BSA bovine serum albumin    -   CatCart® catalytic cartridge    -   CDI 1,1-carbonyl-diimidazole    -   COPD chronic obstructive pulmonary disease    -   d doublet    -   dba dibenzylideneacetone    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCC dicyclohexylcarbodiimide    -   DCM dichloromethane    -   DIAD diisopropyl azodicarboxylate    -   DIPEA diisopropylethylamine    -   DMAP 4-dimethylaminopyridine    -   DMEM Dulbecco's modified eagle medium    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   DPPA diphenylphosphoryl azide    -   d-U937 cells PMA differentiated U-937 cells    -   EDTA ethylenediaminetetraacetic acid    -   ELISA enzyme-linked immunosorbent assay    -   (ES⁻) electrospray ionization, negative mode    -   (ES⁺) electrospray ionization, positive mode    -   Et ethyl    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   FACS fluorescence-activated cell sorting    -   FBS foetal bovine serum    -   FCS foetal calf serum    -   fMLP formyl-methionyl-leucyl-phenylalanine    -   FRET fluorescence resonance energy transfer    -   GSK3α glycogen synthase kinase 3α    -   HBEC primary human bronchial epithelial cells    -   HBSS Hank's balanced salt solution    -   HPLC high performance liquid chromatography    -   HPMC hydroxypropylmethylcellulose    -   h or hr hour(s)    -   HATU 2-(1H-7-azabenzotriazol-1-yl)-1, 1,3,3-tetramethyl uronium        hexafluorophosphate    -   HOAt 1-hydroxy-7-azabenzotriazole    -   HOBt hydroxybenzotriazole    -   HRP horseradish peroxidise    -   HRV human rhinovirus    -   ICAM-1 inter-cellular adhesion molecule 1    -   IFNγ interferon-γ    -   IL interleukin    -   iPrOAc isopropyl acetate    -   JNK c-Jun N-terminal kinase    -   LC liquid chromatography    -   Lck lymphocyte-specific protein tyrosine kinase    -   LiHMDS lithium bis(trimethylsilyl)amide    -   LPS lipopolysaccharide    -   m multiplet    -   (M+H)⁺ protonated molecular ion    -   MAPK mitogen-activated protein kinase    -   MAPKAP-K2 mitogen-activated protein kinase-activated protein        kinase-2    -   mCPBA meta-chloroperbenzoic acid    -   Me methyl    -   MeCN acetonitrile    -   MeOH methanol    -   MHz megahertz    -   min or mins minute(s)    -   MMAD mass median aerodynamic diameter    -   MOI multiplicity of infection    -   MPO myeloperoxidase    -   MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide    -   MS mass spectrometry    -   m/z mass-to-charge ratio    -   NMP N-methyl pyrrolidinone    -   NMR nuclear magnetic resonance (spectroscopy)    -   OD optical density    -   PBMC peripheral blood mononuclear cell    -   PBS phosphate buffered saline    -   Ph phenyl    -   PHA phytohaemagglutinin    -   PMA phorbol myristate acetate    -   pTSA 4-methylbenzenesulfonic acid (para-toluenesulfonic acid)    -   PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   q quartet    -   rt or RT room temperature    -   RP HPLC reverse phase high performance liquid chromatography    -   rpm revolutions per minute    -   RPMI Roswell Park Memorial Institute    -   RSV respiratory syncytial virus    -   s singlet    -   sat or satd saturated    -   SCID severe combined immunodeficiency    -   SCX solid supported cation exchange (resin)    -   SDS sodium dodecyl sulfate    -   S_(N)Ar nucleophilic aromatic substitution    -   Syk Spleen tyrosine kinase    -   t triplet    -   T3P 1-propanephosphonic acid cyclic anhydride    -   TBAI tetrabutylammonium iodide    -   TBAF tetrabutylammonium fluoride    -   TBDMS tert-butyldimethylsilyl    -   TBME tert-butyl methyl ether    -   TBSCl tert-butyldimethylsilyl chloride    -   tBuXPhos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl    -   TCID₅₀ 50% tissue culture infectious dose    -   TEA triethylamine    -   THF tetrahydrofuran    -   TFA trifluoroacetic acid    -   TGFβ transforming growth factor beta    -   TIPS triisopropylsilyl    -   TMB 3,3′,5,5′-tetramethylbenzidine    -   TMS-Cl trimethylsilyl chloride    -   TNFα tumor necrosis factor alpha

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

The invention claimed is:
 1. A compound of formula I,

wherein: T represents:

W represents O, S or NCH₃; V represents N or CR¹; R¹ represents C₁₋₃alkoxy, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, which latter four groupsare optionally substituted by one or more substituents selected from thegroup consisting of halo, hydroxy and C₁₋₂ alkoxy, or R¹ represents H;R² represents —NR^(A1)S(O)₂R^(B1), —S(O)₁₋₂R^(B2), —P(O)R^(B3)R^(B4),C(O)NR^(A2)R^(A3) or —CH₂NR^(A4)C(O)R^(A5); R^(A1) to R^(A5)independently represent H or C₁₋₃ alkyl optionally substituted by one ormore substituents selected from the group consisting of halo, hydroxy,NR^(C)R^(D) and C₁₋₂ alkoxy, or R^(A2) and R^(A3) together representC₃₋₆ n-alkylene or C₄₋₅ n-alkylene interrupted between C2 and C3 by —O—,—S(O)_(q)— or —N(R^(E))—; R^(B1) to R^(B4) independently represent C₁₋₃alkyl or C₃₋₆ cycloalkyl, which latter two groups are optionallysubstituted by one or more halo substituents; R^(C) and R^(D)independently represent H or C₁₋₃ alkyl, which latter substituent isoptionally substituted by hydroxyl or C₁₋₂ alkoxy, or R^(C) and R^(D)together combine to form C₄₋₆ alkylene optionally interrupted between C2and C3 by —O—, —S(O)_(q)— or —N(R^(E))—; R^(E) represents H or methyl; qrepresents 0, 1 or 2; R³ represents C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl or C₃₋₇ cycloalkyl, which latter four groups are optionallysubstituted by hydroxyl, C₁₋₂ alkoxy or halo, or R³ representsmorpholinyl or trimethylsilyl; A represents CH or N; R⁴ represents C₁₋₃alkoxy, C₃₋₅ cycloalkoxy, or C₁₋₃ alkyl, which latter three groups areoptionally substituted by one or more halo substituents, or R⁴represents ethynyl, cyano, S(O)₂CH₃, halo or H; Q represents O,S(O)_(p), SO₂N(R⁶) or C(O)N(R⁶); n represents 1, 2 or 3; p represents 0,1 or 2; R^(5a) and R^(5b) independently represent H, methyl or halo, orR^(5a) and R^(5b) together represent C₂₋₆ n-alkylene; when n represents1, Z represents O, S or NR⁷ or, when n represents 2 or 3, Z representseither an O-atom on each occurrence, or either an S-atom or NR⁷ on oneoccurrence and an O-atom on each other occurence; R⁶ and R⁷independently represent H or methyl; G represents—[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H or a carboxylic acid isostere; r represents0 or, when Het¹ is attached to (CH₂)_(r) via a ring heteroatom, r mayalternatively represent 1; and Het¹ represents a 5- or 6-memberedheterocyclic group that is fully aromatic, which group contains one ormore heteroatoms selected from the group consisting of N, O and S or a4- to 7-membered heterocyclic group that is fully saturated or partiallyunsaturated, and is monocyclic or is fused or bridged bicyclic, whichgroup contains one or more heteroatoms selected from the groupconsisting of N, O and S, wherein Het¹ is optionally substituted by oneor more substituents selected from the group consisting of C₁₋₃ alkyl,C₁₋₃ alkoxy, halo, hydroxyl and oxo, or a pharmaceutically acceptablesalt thereof.
 2. A compound of formula Iy,

or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 2 that is2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid.
 4. A compound as claimed in claim 1 that is a compound of formulaIx or Ia,

wherein R¹ to R⁴, R^(5a), R^(5b), A, Q and n are defined in claim 1, ora pharmaceutically acceptable salt thereof.
 5. A compound as claimed inclaim 1 that is a compound of formula Ib,

wherein R², A, Q and n are defined in claim 1, or a pharmaceuticallyacceptable salt thereof.
 6. A compound as claimed in claim 1, wherein:R¹ represents methoxy or deuterated methoxy; R³ representstrimethylsilyl or —C(CH₃)₂-R, wherein R represents ethynyl or methyl;and/or R⁴ represents cyclopropoxy or methoxy, which latter group isoptionally substituted by one or more halo substituents.
 7. A compoundas claimed in claim 1, wherein R² represents —C(O)NH₂, —C(O)NHCH₃,—S(O)₁₋₂CH₃, —S(O)₁₋₂CH₂CH₃, —P(O)(CH₃)₂, —N(CH₃)S(O)₂CH₃,—NHS(O)₂CH₂CH₃ or —NHS(O)₂CH₃.
 8. A compound as claimed in claim 1,wherein A represents CH.
 9. A compound as claimed in claim 1, wherein Qrepresents C(O)NH, S(O), S(O)₂ or O.
 10. A compound as claimed in claim1, wherein: n represents 2; R^(5a) and R^(5b) independently represent Hor methyl or R^(5a) and R^(5b) together represent —(CH₂)₂—; and/or Grepresents —CO₂H or -Het¹-CO₂H, wherein the -Het¹-CO₂H moiety is astructural fragment selected from the group consisting of:

or G represents a carboxylic acid isostere selected from the groupconsisting of tetrazolyl, —C(O)N(H)—S(O)₂CH₃, —C(O)N(H)—S(O)₂N(CH₃)₂,

or a tautomer of any of the latter three groups.
 11. A compound asclaimed in claim 1, wherein: R² represents —NHS(O)₂CH₃; Q representsC(O)NH or O; and n represents
 2. 12. A compound as claimed in claim 1which is a compound selected from the group consisting of:2-(2-(2-(3-((4-((4-(3-(5-(tert-butyI)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyI)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)aceticacid;2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfinyl)ethoxy)ethoxy)aceticacid;2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)aceticacid;2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethyl)phenoxy)ethoxy)ethoxy)aceticacid;6-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)pyridazine-3-carboxylicacid;5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-1,2,4-oxadiazole-3-carboxylicacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-cyclopropoxyphenoxy)ethoxy)ethoxy)aceticacid;1-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)cyclopropane-1-carboxylicacid;4-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-2-carboxylicacid;1-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-3-methyl-1H-pyrazole-4-carboxylicacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethylphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-(methoxy-d3)-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-N-(methylsulfonyl)acetamide;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(dimethylphosphoryl)-2-methoxyphenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)furan-3-carboxylicacid;5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)tetrahydrofuran-3-carboxylicacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(ethylsulfonyl)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-3-(ethylsulfonamido)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-y1)amino)-5-methoxyphenoxy)ethoxy)ethoxy)aceticacid;N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-2,5-dihydroisoxazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide;2-((2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)thio)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid, (R)-isomer;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoicacid, (S)-isomer;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-2-methylpropanoicacid;1-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylicacid;N-(3-(3-(4-((2-((3-(2-(2-((1H-tetrazol-5-yl)methoxy)ethoxy)ethoxy)-5-methoxyphenyl)amino)-pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)methanesulfonamide;2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)-N-(N,N-dimethylsulfamoyl)acetamide;5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-2-carboxylicacid;5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)thiophene-3-carboxylicacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(difluoromethoxy)phenoxy)ethoxy)ethoxy)aceticacid;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynylphenoxy)ethoxy)ethoxy)aceticacid;N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethoxy)phenoxy)ethoxy)ethoxy)aceticacid;N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-((3-oxo-2,3-dihydroisoxazol-5-yl)methoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide;and5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-1-methyl-1H-pyrrole-2-carboxylicacid, and a pharmaceutically acceptable salt thereof.
 13. Apharmaceutical formulation comprising a compound as defined in claim 1,or a pharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable adjuvant, diluent or carrier.
 14. Apharmaceutical formulation comprising a compound as defined in claim 2,or a pharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable adjuvant, diluent or carrier.
 15. Acombination product comprising (A) a compound as defined in claim 1, ora pharmaceutically acceptable salt thereof, and (B) another therapeuticagent, wherein each of components (A) and (B) is formulated in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier.
 16. Acombination product comprising (A) a compound as defined in claim 2, ora pharmaceutically acceptable salt thereof, and (B) another therapeuticagent, wherein each of components (A) and (B) is formulated in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier.
 17. Amethod of treating an inflammatory disease, said method comprisingadministering to a subject an effective amount of a compound as definedin claim 1, or pharmaceutically acceptable salt thereof, or apharmaceutical formulation comprising a compound as defined in claim 1,or a pharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable adjuvant, diluent or carrier, or acombination product comprising: (A) a compound as defined in claim 1, ora pharmaceutically acceptable salt thereof, and (B) another therapeuticagent, wherein each of components (A) and (B) is formulated in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier.
 18. Amethod of treating an inflammatory disease, said method comprisingadministering to a subject an effective amount of a compound as definedin claim 2, or pharmaceutically acceptable salt thereof, or apharmaceutical formulation comprising a compound as defined in claim 2,or a pharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable adjuvant, diluent or carrier, or acombination product comprising: (A) a compound as defined in claim 2, ora pharmaceutically acceptable salt thereof, and (B) another therapeuticagent, wherein each of components (A) and (B) is formulated in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier.
 19. Amethod according to claim 17, wherein the inflammatory disease isselected from the group consisting of cystic fibrosis, pulmonaryhypertension, lung sarcoidosis, idiopathic pulmonary fibrosis, COPD,chronic bronchitis, emphysema, asthma, paediatric asthma, atopicdermatitis, allergic dermatitis, contact dermatitis or psoriasis,allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergicconjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia,glaucoma, diabetic retinopathy, macular oedema, diabetic macular oedema,central retinal vein occlusion (CRVO), dry and/or wet age relatedmacular degeneration (AMD), post-operative cataract inflammation,uveitis, posterior uveitis, anterior uveitis, pan uveitis, corneal graftand limbal cell transplant rejection, gluten sensitive enteropathy(coeliac disease), eosinophilic esophagitis, intestinal graft versushost disease, Crohn's disease and ulcerative colitis.
 20. A methodaccording to claim 18, wherein the inflammatory disease is selected fromthe group consisting of cystic fibrosis, pulmonary hypertension, lungsarcoidosis, idiopathic pulmonary fibrosis, COPD, chronic bronchitis,emphysema, asthma, paediatric asthma, atopic dermatitis, allergicdermatitis, contact dermatitis or psoriasis, allergic rhinitis,rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis,keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, diabeticretinopathy, macular oedema, diabetic macular oedema, central retinalvein occlusion (CRVO), dry and/or wet age related macular degeneration(AMD), post-operative cataract inflammation, uveitis, posterior uveitis,anterior uveitis, pan uveitis, corneal graft and limbal cell transplantrejection, gluten sensitive enteropathy (coeliac disease), eosinophilicesophagitis, intestinal graft versus host disease, Crohn's disease andulcerative colitis.
 21. A method according to claim 19, wherein theinflammatory disease is uveitis, keratoconjunctivitis sicca, dry eye,xerophthalmia, Crohn's disease or ulcerative colitis.
 22. A methodaccording to claim 20, wherein the inflammatory disease is uveitis,keratoconjunctivitis sicca, dry eye, xerophthalmia, Crohn's disease orulcerative colitis.
 23. A process for the preparation of a compound offormula I, as defined in claim 1, which process comprises: (a) forcompounds of formula I in which G represents—[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H, hydrolysis or hydrogenolysis of an ester offormula I(P),

wherein R^(x) represents C₁₋₆ alkyl or benzyl, respectively, and T, R⁴,R^(5a), R^(5b), A, Q, Z, n, r and Het¹ are as defined in claim 1; (b)reaction of a compound of formula II,

with a compound of formula III,

wherein one of Z¹ and Z² is a structural fragment of formula IVa or IVb,

and the other of Z¹ and Z² is a structural fragment of formula V,

wherein W, V, R¹ to R⁴, R^(5a), R^(5b), A, Q, Z, G and n are as definedin claim 1; (c) reaction of a compound of formula IIa,

 wherein Z¹ is as defined above, with a suitable azide-forming agent,which reaction is followed, without isolation, by thermal rearrangementof the intermediate acyl azide (of formula Z¹—C(O)—N₃) to provide, insitu, a compound of formula II, which compound is then reacted with acompound of formula III as defined above; (d) reaction of a compound offormula IIb,

wherein LG¹ represents a leaving group and Z¹ is as defined above, witha compound of formula III, as defined above; (e) reaction of a compoundof formula VI,

wherein LG² represents a leaving group and R¹ to R³ and A are as definedin claim 1, with a compound of formula VII,

wherein R⁴, R^(5a), R^(5b), Q, Z, G and n are as defined in claim 1; (f)for compounds of formula I in which Q represents S(O)₁₋₂, oxidation of acorresponding compound of formula I in which Q represents S; (g) forcompounds of formula I in which Q represents C(O)NH, reaction of acompound of formula VIII,

wherein LG³ represents OH, OR^(x) or a leaving group, R^(x) is asdefined above and R¹ to R³, and A are as defined in claim 1, with acompound of formula IX,

wherein R^(5a), R^(5b), Z, G and n are as defined in claim 1; (h) forcompounds of formula I in which G represents—[(CH₂)_(r)-Het¹]₀₋₁-C(O)₂H, oxidation of an alcohol of formula Xa,

wherein T, R⁴, R^(5a), R^(5b), A, Q, Z, n, r and Het¹ are as defined inclaim 1; or (i) for compounds of formula I in which G represents—C(O)N(H)OH, —C(O)N(H)OCH₃, —C(O)N(H)-S(O)₂CH₃ or—C(O)N(H)—S(O)₂N(CH₃)₂, coupling of a corresponding compound of formulaI in which G represents —CO₂H with hydroxylamine, methoxyamine,methanesulfonamide or dimethylsulfamide, respectively; (k) for compoundsof formula I in which G represents a hydroxy-substituted isoxazolehaving the structure:

reaction of a compound of formula Xb,

wherein T, A, R⁴, R^(5a), R^(5b), Q, Z and n are as defined in claim 1and R^(x) is as defined above, with hydroxylamine; (l) for compounds offormula I in which G represents tetrazol-5-yl, reaction of a compound offormula Xc,

wherein T, A, R⁴, R^(5a), R^(5b), Q, Z, and n are as defined in claim 1,with a source of azide; (m) for compounds of formula I in which Grepresents 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, reaction of acompound of formula Xc, as defined above, with hydroxylamine, followedby reaction of the resulting N-hydroxyamidine (amidoxime) compound witha —C(O)— source; (n) deprotection of a protected derivative of acompound of formula I, wherein the protected derivative bears aprotecting group on an O- or N-atom of the compound of formula I.